Cycloalkano-indole and -azaindole derivatives

ABSTRACT

Cycloalkano-indole and -azaindole derivatives are prepared by reaction of appropriately substituted carboxylic acids with amines. The cycloalkano-indole and -azaindole derivatives are suitable as active compounds for medicaments, preferably antiatherosclerotic medicaments.

[0001] The present invention relates to cycloalkano-indole and-azaindole derivatives, processes for their preparation and their use asmedicaments, in particular as antiatherosclerotic medicaments.

[0002] It is known that increased blood levels of triglycerides(hypertriglyceridaemia) and cholesterol (hypercholesterolaemia) areassociated with the genesis of atherosclerotic vessel wall changes andcoronary heart diseases.

[0003] A distinctly increased risk of the development of coronary heartdisease is moreover present if these two risk factors occur incombination, which is accompanied, in turn, with an overproduction ofapolipoprotein B-100. There is therefore, as before, a great need tomake available effective medicaments for the control of atherosclerosisand coronary heart diseases.

[0004] The present invention relates to cycloalkano-indole and-azaindole derivatives of the general formula (I)

[0005] in which

[0006] R¹ and R², including the double bond connecting them, togetherform a phenyl or pyridyl ring or a ring of the formula

[0007] wherein

[0008] R⁸ denotes hydrogen or straight-chain or branched allot having upto 4 carbon atoms,

[0009] R³ and R⁴, including the double bond connecting them, togetherform a phenol ring or a 4- to 8-membered cycloalkene or oxocycloalkeneradical,

[0010] all ring systems mentioned under R¹/R² and R³/R⁴ optionally beingsubstituted up to 3 times by identical or different halogen,trifluoromethyl, carboxyl or hydroxyl substituents, by straight-chain orbranched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or bystraight-chain or branched alkyl having up to 6 carbon atoms, which, forits part, can be substituted by hydroxyl or by straight-chain orbranched alkoxy having up to 4 carbon atoms,

[0011] D represents hydrogen, cycloalkyl having 4 to 12 carbon atoms orstraight-chain or branched alkyl having up to 12 carbon atoms,

[0012] E represents the —CO— or —CS— group,

[0013] L represents an oxygen or sulphur atom or a group of the formula—NR⁹,

[0014] wherein

[0015] R⁹ denotes hydrogen or straight-chain or branched alkyl having upto 6 carbon atoms, which is optionally substituted by hydroxyl orphenyl,

[0016] R⁵ represents phenyl or a 5- to 7-membered saturated orunsaturated heterocycle having up to 3 heteroatoms from the seriesconsisting of S, N and/or O, the cycles optionally being substituted upto 3 times by identical or different nitro, carboxyl, halogen or cyanosubstituents or by straight-chain or branched alkenyl or alkoxycarbonyleach having up to 6 carbon atoms or by straight-chain or branched alkylhaving up to 6 carbon atoms, which is optionally substituted byhydroxyl, carboxyl or by straight-chain or branched alkoxy oralkoxycarbonyl each having up to 6 carbon atoms,

[0017] and/or the cycles optionally being substituted by a croup of theformula —OR¹⁰ or —NR¹¹R¹²,

[0018] wherein

[0019] R¹⁰ denotes hydrogen or straight-chain or branched alkyl oralkenyl each having up to 6 carbon atoms,

[0020] R¹¹ and R¹² are identical or different and denote phenyl,hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms

[0021] or straight-chain or branched acyl having up to 8 carbon atoms,which is optionally substituted by a group of the formula —NR¹³R¹⁴,

[0022] wherein

[0023] R¹³ and R¹⁴ are identical or different and denote hydrogen orstraight-chain or branched acyl having up to 8 carbon atoms,

[0024] R⁶ represents hydrogen, carboxyl or straight-chain or branchedalkoxycarbonyl having up to 5 carbon atoms,

[0025] or represents straight-chain or branched alkyl having up to 6carbon atoms, which is optionally substituted by hydroxyl or by a groupof the formula —O—CO—R¹⁵,

[0026] wherein

[0027] R¹⁵ denotes phenyl which is optionally substituted up to 3 timesby identical or different halogen or hydroxyl substituents or bystraight-chain or branched alkyl having up to 5 carbon atoms,

[0028] or straight-chain or branched alkyl or alkenyl each having up to22 carbon atoms, each of which is optionally substituted by a group ofthe formula —OR¹⁶,

[0029] wherein

[0030] R¹⁶ is hydrogen, benzyl, triphenylmethyl or straight-chain orbranched acyl having up to 6 carbon atoms,

[0031] R⁷ represents hydrogen or

[0032] R⁶ and R⁷ together represent the group of the formula ═O,

[0033] if appropriate in an isomeric form, and their salts.

[0034] The cycloalkano-indole and -azaindole derivatives according tothe invention can also be present in the form of their salts. Ingeneral, salts with organic or inorganic bases or acids may be mentionedhere.

[0035] In the context of the present invention, physiologicallyacceptable salts are preferred. Physiologically acceptable salts of thecompounds according to the invention can be salts of the substancesaccording to the invention with mineral acids, carboxylic acids orsulphonic acids. Particularly preferred salts are, for example, thosewith hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoricacid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonicacid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid,propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid,maleic acid or benzoic acid.

[0036] Physiologically acceptable salts can also be metal or ammoniumsalts of the compounds according to the invention which have a freecarboxyl group. Particularly preferred salts are, for example, sodium,potassium, magnesium or calcium salts, and also ammonium salts which arederived from ammonia, or organic amines, such as, for exampleethylamine, di- or triethylamine, di- or triethanolamine,dicyclohexylamine, dimethylaminoethanol, arginine, lysine,ethylenediamine or 2-phenylethylamine.

[0037] Including the double bond of parent structure, the cycloalkeneradical (R³/R⁴) in the context of the invention in general represents a4- to 8-membered hydrocarbon radical, preferably a 5- to 8-memberedhydrocarbon radical, for example a cyclobutene, cyclopentene,cyclohexene, cycloheptene or cyclooctene radical. The cyclopentene,cyclohexene, cyclooctene or cycloheptene radicals are preferred.

[0038] Heterocycle (R⁵) in the context of the invention in generalrepresents a saturated or unsaturated 5- to 7-membered heterocycle,preferably a 5- to 6-membered heterocycle, which can contain up to 3heteroatoms from the series consisting of S, N and/or O. Examples whichmay be mentioned are: pyridyl, thienyl, furyl, pyrrolyl, thiazolyl,oxazolyl, imidazolyl, morpholinyl or piperidyl. Pyridyl and thienyl arepreferred.

[0039] The compounds according to the invention can exist instereoisomeric forms which either behave as image and mirror image(enantiomers), or do which do not behave as image and mirror image(diastereomers). The invention relates both to the enantiomers anddiastereomers and their respective mixtures. These mixtures of theenantiomers and diastereomers can be separated in a known manner intothe stereoisomerically uniform constituents.

[0040] Preferred compounds of the general formula (I) are those

[0041] in which

[0042] R¹ and R², including the double bond connecting them, togetherform a phenyl or pyridyl ring or a ring of the formula

[0043] wherein

[0044] R⁸ denotes hydrogen or straight-chain or branched alkyl having upto 3 carbon atoms,

[0045] R³ and R⁴, including the double bond connecting them, togetherform a phenyl ring or a cyclopentene, cyclohexene, cycloheptene,cyclooctene, oxocyclopentene, oxocyclohexene, oxocycloheptene oroxocyclooctene radical,

[0046] all ring systems mentioned under R¹/R² and R³/R⁴ optionally beingsubstituted up to 2 times by identical or different fluorine, chlorine,bromine, trifluoromethyl, carboxyl or hydroxyl substituents, bystraight-chain or branched alkoxy or alkoxycarbonyl each having up to 4carbon atoms or by straight-chain or branched alkyl having up to 4carbon atoms, which, in turn, can be substituted by hydroxyl or bystraight-chain or branched alkoxy having up to 3 carbon atoms.

[0047] D represents hydrogen, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl or straight-chain or branched alkyl having up to10 carbon atoms,

[0048] E represents the —CO— or —CS— group,

[0049] L represents an oxygen or sulphur atom or represents a group ofthe formula —NR⁹,

[0050] wherein

[0051] R⁹ denotes hydrogen or straight-chain or branched alkyl having upto 5 carbon atoms, which is optionally substituted by hydroxyl orphenyl,

[0052] R⁵ represents phenyl, pyridyl, furyl, thienyl or imidazolyl, eachof which is optionally substituted up to 2 times by identical ordifferent nitro, carboxyl, fluorine, chlorine, bromine or cyanosubstituents, by straight-chain or branched alkenyl or alkoxy carbonyleach having up to 4 carbon atoms or by straight-chain or branched alkylhaving up to 5 carbon atoms, which is optionally substituted byhydroxyl, carboxyl or by straight-chain or branched alkoxy oralkoxycarbonyl each having up to 5 carbon atoms,

[0053] and/or the cycles are optionally substituted by a group of theformula —OR¹⁰ or —NR¹¹R¹²,

[0054] wherein

[0055] R¹⁰ denotes hydrogen or straight-chain or branched alkyl oralkenyl each having up to 4 carbon atoms,

[0056] R¹¹ and R¹² are identical or different and denote phenyl,hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms

[0057] or denote straight-chain or branched acyl having up to 6 carbonatoms, which is optionally substituted by a group of the formula—NR¹³R¹⁴,

[0058] wherein

[0059] R¹³ and R¹⁴ are identical or different and denote hydrogen orstraight-chain or branched acyl having up to 6 carbon atoms,

[0060] R⁶ represents hydrogen, carboxyl or straight-chain or branchedalkoxycarbonyl having up to 4 carbon atoms,

[0061] or represents straight-chain or branched alkyl having up to 5carbon atoms, which is optionally substituted by hydroxyl or by a groupof the formula —O—CO—R¹⁵,

[0062] wherein

[0063] R¹⁵ denotes phenyl which is optionally substituted up to 3 timesby identical or different fluorine, chlorine, bromine or hydroxylsubstituents or by straight-chain or branched alkyl having up to 4carbon atoms,

[0064] or straight-chain or branched alkyl or alkenyl each having up to20 carbon atoms, each of which is optionally substituted by a group ofthe formula —OR¹⁶,

[0065] wherein

[0066] R¹⁶ is hydrogen, benzyl, triphenylmethyl or straight-chain orbranched acyl having up to 5 carbon atoms,

[0067] R⁷ represents hydrogen or

[0068] R⁶ and R⁷ together represent the group of the formula ═O,

[0069] if appropriate in an isomeric form, and their salts.

[0070] Particularly preferred compounds of the general formula (I) arethose in which

[0071] R¹ and R², including the double bond connecting them, togetherform a phenyl or pyridyl ring or a ring of the formula

[0072] wherein

[0073] R⁸ denotes hydrogen or methyl,

[0074] R³ and R⁴, including the double bond connecting them, togetherform a phenyl ring or a cyclopentene, cyclohexene, cycloheptene,cyclooctene, oxocyclopentene, oxocyclohexene, oxocycloheptene oroxocyclooctene radical,

[0075] all ring systems mentioned under R¹/R² and R³/R⁴ optionally beingsubstituted up to 2 times by identical or different fluorine, chlorine,bromine, trifluoromethyl, carboxyl or hydroxyl substituents, bystraight-chain or branched alkoxy or alkoxycarbonyl each having up to 3carbon atoms or by straight-chain or branched alkyl having up to 3carbon atoms, which, for its part, can be substituted by hydroxyl,methoxy or ethoxy,

[0076] D represents hydrogen, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl or straight-chain or branched alkyl having up to 6 carbonatoms,

[0077] E represents the —CO— or —CS— group,

[0078] L represents an oxygen or sulphur atom or represents a group ofthe formula —NR⁹,

[0079] wherein

[0080] R⁹ denotes hydrogen or straight-chain or branched alkyl having upto 4 carbon atoms, which is optionally substituted by hydroxyl orphenyl,

[0081] R⁵ represents phenyl, pyridyl or thienyl, each of which isoptionally substituted up to 2 times by identical or different nitro,carboxyl, fluorine, chlorine, bromine or cyano substituents, bystraight-chain or branched alkenyl or alkoxycarbonyl each having up to 3carbon atoms or by straight-chain or branched alkyl having up to 4carbon atoms, which is optionally substituted by hydroxyl, carboxyl orby straight-chain or branched alkoxy or alkoxycarbonyl each having up to4 carbon atoms,

[0082] and/or the cycles are optionally substituted by a group of theformula —OR¹⁰ or —NR¹¹R¹²,

[0083] wherein

[0084] R¹⁰ denotes hydrogen or straight-chain or branched alkyl oralkenyl each having up to 3 carbon atoms,

[0085] R¹¹ and R¹² are identical or different and denote phenyl,hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms

[0086] or denote straight-chain or branched acyl having up to 5 carbonatoms, which is optionally substituted by a group of the formula—NR¹³R¹⁴,

[0087] wherein

[0088] R¹³ and R¹⁴ are identical or different and denote hydrogen orstraight-chain or branched acyl having up to 5 carbon atoms,

[0089] R⁶ represents hydrogen, carboxyl or straight-chain or branchedalkoxycarbonyl having up to 3 carbon atoms,

[0090] or represents straight-chain or branched alkyl having up to 4carbon atoms, which is optionally substituted by hydroxyl or by a groupof the formula —O—CO—R¹⁵,

[0091] wherein

[0092] R¹⁵ denotes phenyl which is optionally substituted up to 3 timesby identical or different straight-chain or branched alkyl having up to3 carbon atoms,

[0093] or denotes straight-chain or branched alkyl or alkenyl eachhaving up to 19 carbon atoms, each of which is optionally substituted bya group of the formula —OR¹⁶,

[0094] wherein

[0095] R¹⁶ denotes hydrogen, benzyl, triphenylmethyl or straight-chainor branched acyl having up to 4 carbon atoms,

[0096] R⁷ represents hydrogen or

[0097] R⁶ and R⁷ together represent the group of the formula ═O,

[0098] if appropriate in an isomeric form and their salts.

[0099] A process for the preparation of the compounds of the generalformula (I) according to the invention has additionally been found,characterized in that

[0100] carboxylic acids of the general formula (II)

[0101] in which

[0102] R¹, R², R³, R⁴ and D have the meaning indicated,

[0103] are amidated using compounds of the general formula (III)

[0104] in which

[0105] R⁵ has the meaning indicated

[0106] and

[0107] R¹⁷ has the indicated meaning of R⁶, but does not representcarboxyl,

[0108] in an inert solvent and in the presence of bases and/orauxiliaries,

[0109] and, if appropriate, functional groups are varied by hydrolysis,esterification or reduction.

[0110] The process according to the invention can be illustrated by thefollowing reaction scheme:

[0111] Suitable solvents for the amidation are in this case inertorganic solvents which do not change under the reaction conditions.These include ethers, such as diethyl ether or tetrahydrofuran,halogenohydrocarbons such as dichloromethane, trichloromethane,tetrachloromethane, trichloroethane, tetrachloroethane,1,2-dichloroethane or trichloroethylene, hydrocarbons such as benzene,xylene, toluene, hexane, cyclohexane or petroleum fractions,nitromethane, dimethylformamide, acetone, acetonitrile orhexamethylphosphoramide. It is also possible to employ mixtures of thesolvents. Dichloromethane, tetrahydrofuran, acetone anddimethylformamide are particularly preferred.

[0112] Bases which can be employed for the process according to theinvention are in general inorganic or organic bases. These preferablyinclude alkali metal hydroxides such as, for example, sodium hydroxideor potassium hydroxide, alkaline earth metal hydroxides, such as, forexample, barium hydroxide, alkali metal carbonates such as sodiumcarbonate or potassium carbonate, alkaline earth metal carbonates suchas calcium carbonate, or alkali metal alkoxides such as sodium orpotassium methoxide, sodium or potassium ethoxide or potassiumtert-butoxide, or organic amines (trialkyl(C₁-C₆)amines) such astriethylamine, or heterocycles such as 1,4-diazabicyclo[2.2.2]octane(DABCO), 1.8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine,diaminopyridine, methylpiperidine or morpholine. It is also possible toemploy alkali metals such as sodium and their hydrides such as sodiumhydride as bases. Sodium and potassium carbonate and triethylamine arepreferred.

[0113] The base is employed in an amount from 1 mol to 5 mol, preferablyfrom 1 mol to 3 mol, relative to 1 mol of the compound of the generalformula (II).

[0114] The reaction is in general carried out in a temperature rangefrom 0° C. to 150° C., preferably from +20° C. to +110° C.

[0115] The reaction can be carried out at normal, increased or reducedpressure (e.g. 0.5 to 5 bar). In general, the reaction is carried out atnormal pressure.

[0116] The amidation can optionally proceed via the activated stage ofthe acid halides, which can be prepared from the corresponding acids byreaction with thionyl chloride, phosphorus trichloride, phosphoruspentachloride, phosphorus tribromide or oxalyl chloride.

[0117] The abovementioned bases can optionally also be employed for theamidation as acid-binding auxiliaries.

[0118] Suitable auxiliaries are also dehydrating reagents. Theseinclude, for example, carbodiimides such as diisopropylcarbodiimide,dicyclohexylcarbodiimide andN-(3-dimethylaminopropl)N′-ethylcarbodiimide hydrochloride or carbonylcompounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as2-ethyl-5-phenyl-1,2-oxazolium-3-sulphonate or propanephosphonicanhydride or iso-butyl chloroformate orbenzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate ordiphenyl phosphoramidate or methanesulphonyl chloride, if appropriate inthe presence of bases such as triethylamine or N-ethylmorpholine orN-methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide.

[0119] The acid-binding agents and dehydrating reagents are in generalemployed in an amount from 0.5 to 3 mol, preferably from 1 to 1.5 mol,relative to 1 mol of the corresponding carboxylic acids.

[0120] The variation of functional groups, for example hydrolysis,esterification and reduction, and also separation of isomers and saltformation is carried out by customary methods.

[0121] The carboxylic acids of the general formula (II) are new and canbe prepared by reacting

[0122] compounds of the general formula (IV)

[0123] in which

[0124] D has the meaning indicated,

[0125] T represents a typical leaving group, for example chlorine,bromine, iodine, tosylate or mesylate, preferably bromine,

[0126] and

[0127] R¹⁸ represents (C₁-C₄)-alkyl,

[0128] with compounds of the general formula (V)

[0129] in which

[0130] R¹, R², R³ and R⁴ have the meaning indicated,

[0131] in inert solvents, if appropriate in the presence of a base.

[0132] Suitable solvents for the process are the customary organicsolvents which do change under the reaction conditions. These preferablyinclude ethers such as diethyl ether, dioxane, tetrahydrofuran, glycoldimethyl ether, or hydrocarbons such as benzene, toluene, xylene,hexane, cyclohexane or petroleum fractions, or halogenohydrocarbons suchas dichloromethane, trichloromethane, tetrachloromethane,dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate,triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide,hexamethylphosphoramide, acetonitrile, acetone or nitromethane. It isalso possible to use mixtures of the solvents mentioned.Dimethylformamide and tetrahydrofuran are preferred.

[0133] The bases employed for the process according to the invention canin general be inorganic or organic bases. These preferably includealkali metal hydroxides, for example, sodium hydroxide or potassiumhydroxide, alkaline earth metal hydroxides, for example, bariumhydroxide, alkali metal carbonates such as sodium carbonate or potassiumcarbonate, alkaline earth metal carbonates such as calcium carbonate, oralkali metal alkoxides such as sodium or potassium methoxide, sodium orpotassium ethoxide or potassium tert-butoxide, or organic amines(trialkyl(C₁-C₆)amines) such as triethylamine, or heterocycles such as1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine,methylpiperidine or morpholine. It is also possible to employ alkalimetals such as sodium or their hydrides such as sodium hydride as bases.Sodium hydride, potassium carbonate, triethylamine, pyridine andpotassium tert-butoxide, DBU or DABCO are preferred.

[0134] In general, the base is employed in an amount from 0.05 mol to 10mol, preferably from 1 mol to 2 mol, relative to 1 mol of the compoundof the formula (IV).

[0135] The process according to the invention is in general carried outin a temperature range from −30° C. to +100° C., preferably from −10C.to +60° C.

[0136] The process according to the invention is in general carried outat normal pressure. However, it is also possible to carry out theprocess at elevated pressure or at reduced pressure (e.g. in a rangefrom 0.5 to 5 bar).

[0137] The compounds of the general formula (III) are known per se.

[0138] The compounds of the general formula (IV) are known or can beprepared in analogy to known methods.

[0139] The compounds of the general formula (V) are known or can beprepared in analogy to known methods.

[0140] The compounds of the general formula (I) according to theinvention have an unforeseeable spectrum of pharmacological action.

[0141] They can be used as active compounds in medicaments for thereduction of changes to vessel walls and for the treatment of coronaryheart disorders, cardiac insufficiency, brain power disorders, ischaemicbrain disorders, apoplexy, circulatory disorders, disorders of themicrocirculation and thromboses.

[0142] Furthermore, the proliferation of smooth muscle cells plays adecisive part in the occlusion of vessels. The compounds according tothe invention are suitable for inhibiting this proliferation and thuspreventing atherosclerotic processes.

[0143] The compounds according to the invention are distinguished by alowering of the ApoB-100-associated lipoproteins (VLDL and itsdegradation products, e.g. LDL), of ApoB-100, of triglycerides and ofcholesterol. They thus have useful, superior pharmacological propertiesin comparison with the prior art.

[0144] Surprisingly, the action of the compounds according to theinvention consists first in a decrease or complete inhibition of theformation and/or the release of ApoB-100-associated lipoproteins fromliver cells, which results in a lowering of the VLDL plasma level. Thislowering of VLDL must be accompanied by a lowering of the plasma levelof ApoB-100, LDL, triglycerides and cholesterol; a number of theabovementioned risk factors which are involved in vessel wall changesare thus simultaneously decreased.

[0145] The compounds according to the invention can therefore beemployed for the prevention and treatment of atherosclerosis, obesity,pancreatitis and constipation.

[0146] I. Inhibition of the Release of ApoB-100-Associated Lipoproteins

[0147] The test for detecting the inhibition of the release ofApoB-100-associated lipoproteins from liver cells was carried out invitro using cultured liver cells, preferably using cells of the humanline HepG2. These cells are cultured under standard conditions in mediumfor the culture of eukaryotic cells, preferably in RPMI 1640 with 10%foetal calf serum. HepG2 cells synthesize and secrete into the culturesupernatant ApoB-100-associated lipoprotein particles which in principleare built up in a similar manner to the VLDL and LDL particles which areto be found in the plasma.

[0148] These particles can be detected using an immunoassay for humanLDL. This immunoassay is carried out using antibodies which have beeninduced against human LDL in rabbits under standard conditions. Theanti-LDL antibodies (rabbit anti-LDL Ab) were purified by affinitychromatography on an immunosorbent using human LDL. These purifiedrabbit anti-LDL Ab are adsorbed on the surface of plastic. Expediently,this adsorption is carried out on the plastic surface of microtitreplates having 96 wells, preferably on MaxiSorp plates. IfApoB-100-associated particles are present in the supernatant of Hep-G2cells, they can be bound to the insolubilized rabbit anti-LDL Ab, and animmune complex results which is bound to the plastic surface. Unboundproteins are removed by washing. The immune complex located on theplastic surface is detected using monoclonal antibodies which have beeninduced against human LDL and purified according to standard conditions.These antibodies were conjugated with the enzyme peroxidase. Peroxidaseconverts the colourless substrate TMB into a coloured product in thepresence of H₂O₂. After acidification of the reaction mixture withH₂SO₄, the specific light absorption at 450 nm is determined, which is ameasure of the amount of ApoB-100-associated particles which have beensecreted into the culture supernatant by the HepG2 cells.

[0149] Surprisingly, the compounds according to the invention inhibitthe release of the ApoB-100-associated particles. The IC₅₀ valueindicates at which substance concentration the light absorption isinhibited by 50% in comparison with the control (solvent control withoutsubstance). Ex. No. IC₅₀ [10⁻⁹ mol/l] 1 28 5 1.1 31 170 50 29

[0150] 2. Determination of the VLDL Secretion in vivo in the Hamster

[0151] The effect of the test substances on VLDL secretion in vivo isinvestigated in the hamster. To do this, golden hamsters areanaesthetized with Ketaset (83 mg/kg s.c.) and Nembutal (50 mg/kg i.p.)after premedication with atropine (83 mg/kg s.c.). When the animals havebecome reflex-free, the jugular vein is exposed and cannulated. 0.25ml/kg of a 20% strength solution of Triton WR-1339 in physiologicalsaline solution is then administered. This detergent inhibits thelipoprotein lipase and thus leads to a rise in the triglyceride level asa result of a lack of catabolism of secreted VLDL particles. Thistriglyceride rise can be used as a measure of the VLDL secretion rate.

[0152] Blood is taken from the animals before and also one and two hoursafter administration of the detergent by puncture of the retroorbitalvenous plexus. The blood is incubated for two hours at room temperature,and then overnight at 4° C., in order to end clotting completely. It isthen centrifuged at 10,000 g for 5 minutes. The triglycerideconcentration in the serum thus obtained is determined with the aid of amodified commercially available enzyme test (Merckotest® triglycerideNo. 14354). 100 μl of serum are treated with 100 μl of test reagent in96-hole plates and incubated at room temperature for 10 minutes. Theoptical density is then determined at a wavelength of 492 nM in anautomatic plate-reading apparatus (SLT Spectra). Serum samples having anexcessively high triglyceride concentration are diluted withphysiological saline solution. The triglyceride concentration containedin the samples is determined with the aid of a standard curve measuredin parallel. In this model, test substances are administeredintravenously either immediately before administration of the detergentor orally or subcutaneously before initiation of anaesthesia. Ex. No.ED₅₀ [mg/kg] p.o. 2 10-15 5 3-6 7 10-20

[0153] 3. Inhibition of Intestinal Triglyceride Absorption in vivo(Rats)

[0154] The substances which are to be investigated for theirtriglyceride absorption-inhibiting action in vivo are administeredorally to male Wistar rats having a body weight of between 170 and 230g. For this purpose, the animals are divided into groups of 6 animals 18hours before substance administration and food is then withdrawn fromthem. Drinking water is available to the animals ad libitum. The animalsof the control groups receive an aqueous tragacanth suspension or atragacanth suspension which contains olive oil. The tragacanth-olive oilsuspension is prepared using an Ultra-Turrax. The substances to beinvestigated are suspended in an appropriate tragacanth-olive oilsuspension likewise using the Ultra-Turrax, directly before substanceadministration.

[0155] To determine the basal serum triglyceride content, blood is takenfrom each rat by puncture of the retroorbital venous plexus beforestomach tube application. The tragacanth suspension, thetragacanth-olive oil suspensions without substance (control animals) orthe substances suspended in an appropriate tragacanth-olive oilsuspension are then administered to the fasting animals using a stomachtube. Further taking of blood to determine the postprandial serumtriglyceride rise is carried out, as a rule, 1, 2 and 3 hours afterstomach tube application.

[0156] The blood samples are centrifuged and, after recovering theserum, the triglycerides are determined photometrically using an EPOSanalyzer 5060 (Eppendorf Gerätebau, Netheler & Hinz GmbH, Hamburg). Thedetermination of the triglycerides is carried out completelyenzymatically using a standard commercial UV test.

[0157] The postprandial serum triglyceride rise is determined bysubtraction of the triglyceride preliminary value of each animals fromits corresponding postprandial triglyceride concentrations (1, 2 and 3hours after administration).

[0158] The differences (in mmol/l) at each point in time (1, 2 and 3hours) are averaged in the groups, and the mean values of the serumtriglyceride rise (ΔTG) of the substance-treated animals is comparedwith the animals which only received the tragacanth-oil suspension.

[0159] The serum triglyceride course of the control animals which onlyreceived tragacanth is also calculated. The substance effect at eachpoint in time (1, 2 and 3 hours) is determined as follows and indicatedin Δ% of the oil-loaded control.${\Delta \quad \% \quad {Triglyceride}\quad {rise}} = {\frac{{\Delta \quad {TG}_{substance}} - {\Delta \quad {TG}_{{tragacanth}\quad {control}}}}{{\Delta \quad {TG}_{{oil}\quad {loading}}} - {\Delta \quad {TG}_{{tragacanth}\quad {control}}}} \times 100}$

[0160] Effect of 10 mg of test substance/kg of body weight p.o. on thetriglyceride rise (Δ%) 2 h after a triglyceride loading in the serum offasting rats. The serum triglyceride rise of fat-loaded control animalsrelative to the serum triglyceride level of tragacanth control animalscorresponds to 100%. n=6 animals per group. Serum triglyceride rise in %(2 h pp) Triglyceride loading 100 Tragacanth control 0 Substance 10mg/kg of body weight p.o. Ex. No. 10 34 Ex. No. 66 67 Ex. No. 54 54 Ex.No. 71 18 Ex. No. 5 −16 Ex. No. 20 35

[0161] Statistical evaluation is carried out using Student's t testafter preliminary checking of the variances for homogeneity.

[0162] Substances which at one point in time statistically significantly(p<0.05) decrease the postprandial serum triglyceride rise by at least30% compared with the untreated control group are rewarded aspharmacologically active.

[0163] 4. Inhibition of VLDL Secretion in vivo (Rats)

[0164] The action of the test substances on VLDL secretion is likewiseinvestigated in the rat. To do this, 500 mg/kg of body weight (2.5mg/kg) of Triton WR-1339, dissolved in physiological saline solution, isadministered intravenously into the tail vein of rats. Triton WR-1339inhibits lipoprotein lipase and thus leads to an increase in thetriglyceride and cholesterol level by inhibition of the VLDL catabolism.These rises can be used as a measure of the VLDL secretion rate.

[0165] Blood is taken from the animals by puncture of the retroorbitalvenous plexus before and also one and two hours after administration ofthe detergent. The blood is incubated at room temperature for 1 h forclotting and the serum is obtained by centrifugation at 10,000 g for 20s. The triglycerides are then photometrically determined by means of astandard commercial coupled enzyme test (Sigma Diagnostics®, No. 339) ata wavelength of 540 nm. Measurement is carried out with the aid of alikewise coupled enzyme test (Boehring Mannheim®, No. 1442350) at awavelength of 546 nm. Samples with triglyceride or cholesterolconcentrations which exceed the measuring range of the methods arediluted with physiological saline solution. The determination of therespective serum concentrations is carried out with the aid of standardseries measured in parallel. Test substances are administered orally,intravenously or subcutaneously immediately after the Triton injection.

[0166] The invention additionally relates to the combination ofcycloalkano-indole and -azaindole derivatives of the general formula (I)with glucosidase and/or amylase inhibitor for the treatment of familialhyperlipidaemia, obesity (adiposity) and diabetes mellitus. Glucosidaseand/or amylase inhibitors in the context of the invention are, forexample, acarbose, adiposine, voglibase, miglitol, emiglitate, MDL25637, camiglibase (MDL 73945), tendamistat, AI-3688, trestatin,pradimilin-Q and salbostatin.

[0167] Combination of acarbose, miglitol, emiglitate or voglibase withone of the abovementioned compounds of the general formula (I) accordingto the invention is preferred.

[0168] The new active compounds can be converted in a known manner intothe customary formulations, such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, non-toxic, pharmaceutically suitable excipients or solvents. Inthis case, the therapeutically active compound should in each case bepresent in a concentration of approximately 0.5 to 90% by weight of thetotal mixture, i.e. in amounts which are sufficient in order to achievethe dosage range indicated.

[0169] The formulations are prepared, for example, by extending theactive compounds with solvents and/or excipients, if appropriate usingemulsifiers and/or dispersants, it optionally being possible, e.g. inthe case of the use of water as a diluent, to use organic solvents asauxiliary solvents.

[0170] Administration is carried out in a customary manner, preferablyorally or parenterally, in particular perlingually or intravenously.

[0171] In the case of parenteral administration, solutions of the activecompound can be employed using suitable liquid vehicles.

[0172] In general, it has proved advantageous in the case of intravenousadminstration to administer amounts of approximately 0.001 to 1 mg/kg ofbody weight, preferably approximately 0.01 to 0.5 mg/kg of body weight,to achieve effective results, and in the case of oral administration thedose is approximately 0.01 to 20 mg/kg of body weight, preferably 0.1 to10 mg/kg of body weight.

[0173] In spite of this, it may optionally be necessary to depart fromthe amounts mentioned, namely depending on the body weight or on thetype of administration route, on individual behaviour towards themedicament, the manner of its formulation and the time or interval atwhich administration takes place. Thus, in some cases it may be adequateto manage with less than the abovementioned minimum amount, while inother cases the upper limit mentioned must be exceeded. In the case ofthe administration of larger amounts, it may be advisable to dividethese into several individual doses over the course of the day.

[0174] Definition of the Isomer Types:

[0175] 4 dia = mixture of the four possible diastereomers in the case oftwo centres of asymmetry in the molecule

[0176] dia A = diastereomer having the larger R_(f) value

[0177] dia B = diastereomer having the smaller R_(f) value

[0178] ent = enantiomer

[0179] 2 ent dia = mixture of two enantiomerically pure diastereomers

[0180] ent dia A = enantiomerically pure diastereomer having the largerR_(f) value

[0181] ent dia B = enantiomerically pure diastereomer having the smallerR_(f) value

[0182] R = R enantiomer

[0183] rac = racemate

[0184] rac dia A = racemic diastereomer having the larger R_(f) value

[0185] rac dia B = racemic diastereomer having the smaller R_(f) value

[0186] S = S enantiomer

[0187] Abbreviations Used:

[0188] Ac = acetyl

[0189] Bn = benzyl

[0190] Bz = benzoyl

[0191] iB = isobutyl

[0192] nBu = normal butyl

[0193] sBu = secondary butyl

[0194] tBu = tertiary butyl

[0195] DDQ = 2,3-dichloro-5,6dicyano-1,4benzoquinone

[0196] cDec = cyclo-decyl

[0197] DMF = N,N-dimethylformamide

[0198] DMSO = dimethyl sulphoxide

[0199] cDodec = cyclo-dodecyl

[0200] Et = ethyl

[0201] cHept = cyclo-heptyl

[0202] cHex = cyclo-hexyl

[0203] HOBT = 1-hydroxy-1H-benzotriazole

[0204] Me = methyl

[0205] Mes = mesyl

[0206] cNon = cyclo-nonyl

[0207] cOct = cyclo-octyl

[0208] cPent = cyclo-pentyl

[0209] nPent = normal pentyl

[0210] Ph = phenyl

[0211] cPr = cyclo-propyl

[0212] nPr = normal propyl

[0213] iPr = isopropyl

[0214] THF = tetrahydrofuran

[0215] TMS = tetramethylsilane

[0216] pTol = para-tolyl

[0217] pTos = para-tosyl

[0218] cUndec = cyclo-undecyl Solvent Symbol Dichloromethane:methanol =20:1 A Dichloromethane:methanol = 50:1 B Dichloromethane:ethanol = 20:1C Dichloromethane:ethanol = 50:1 D Petroleum ether:ethyl acetate = 1:1 EDichloromethane:methanol:acetic acid = 90:10:2 F Petroleum ether:ethylacetate = 2:1 G Petroleum ether:ethyl acetate = 10:1 H Toluene IToluene:ethyl acetate = 1:1 K Petroleum ether:ethyl acetate = 5:1 LDichloromethane M Petroleum ether:ethyl acetate = 20:1 NDichloromethane:methanol 10:1 O Cyclohexane:ethyl acetate = 1:1 PToluene:ethyl acetate = 9:1 Q Toluene:ethyl acetate = 8:1 R Petroleumether:ethyl acetate = 1:2 S Dichloromethane:ethanol = 5:1 TDichloromethane:ethanol = 10:1 U

[0219] Preparation Procedure for the TLC Mobile Phase BABA:

[0220] 87.9 ml of an aqueous 0.06667 molar potassium dihydrogenphosphate solution and 12.1 ml of an aqueous 0.06667 molar disodiumhydrogen phosphate solution are mixed. 60 ml of the solution prepared inthis way are shaken with 200 ml of n-butyl acetate, 36 ml of n-butanoland 100 ml of glacial acetic acid and the aqueous phase is removed. Theorganic phase is the mobile phase BABE.

STARTING COMPOUNDS Example I

[0221] 1-Allyloxy-2-chloromethylbenzene

[0222] 11.5 g (70 mmol) of 1-allyloxy-2-hydroxymethyl-benzene aretreated with 11.6 ml (84 mmol) of triethylamine at 0° C. in 110 ml ofdichloromethane and then slowly reacted with 5.4 ml (70 mmol) ofmethanesulphonyl chloride. After 4 hours, the mixture is extractedseveral times with water, and the organic phase is dried over magnesiumsulphate and evaporated. Residual solvent is removed in a high vacuum.

[0223] Yield: 8.5 g

[0224] R_(f)=0.23 (dichloromethane:ethanol=20:1)

Example II

[0225] (2-Allyloxy-benzyl)amine

[0226] 3.0 g (16.4 mmol) of the compound from Example I are boiled underreflux for 17 hours in 250 ml of a saturated methanolic ammoniasolution. The reaction mixture is evaporated in vacuo, the residue istaken up in methanol and the mixture is evaporated again; this processis repeated a few times. The crude product is taken up indichloromethane and extracted several times with water. The aqueousphase is evaporated to a very great extent, an oil being obtained whichcrystallizes on standing.

[0227] Yield: 0.454 g (crude)

[0228] The product is reacted further without further purification.

[0229] R_(f)=0.41 (mobile phase:BABA)

Example III

[0230] 6-Chloro-2,4-lutidine

[0231] For the preparation of the title compound [U.S. Pat. No.36,32,807], 600 g (4.91 mol) of 6-amino-2,4-lutidine are dissolved in 2l of methanol and the solution is saturated with hydrogen chloride gasat about 0° C. 1.307 l (9.82 mol) of isopentyl nitrite are addeddropwise (about 2.5 h) at an internal temperature of below 10° C. andthe mixture is left in this way for 15 h while warming to roomtemperature (about 25° C.). The solution is largely freed from thesolvent in vacuo, mixed with 3 l of dichloromethane and 1.5 l of waterand adjusted to pH=9.5 while cooling (<20° C.) with concentrated aqueousammonia solution. The separated organic phase is dried with sodiumsulphate, first concentrated in vacuo on a rotary evaporator and thendistilled through a Vigreux column:

[0232] Fraction 1) B.p.=47-49° C. (12 mm Hg), 603 g

[0233] Fraction 2) B.p.=82-85° C. (12 mm Hg), 612 g (about 88% crude)

[0234] R_(f)=0.39 (petroleum ether:ethyl acetate=10:1)

[0235]¹H-NMR (CDCl₃200 MHz, TMS): δ=2.28 (S, 3H), 2.47 (S, 3H), 6.88 (S,1H), 6.96 (S, 1H) ppm.

[0236] The crude product, which may contain small amounts of6-methoxy-2,4-lutidine, is reacted further without further purification.

Example IV

[0237] 6-Hydrazino-2,4-lutidine (4,6-dimethyl-2-hydrazino-pyridine)

[0238] 580 g (4.10 mol) of the compound from Example III are dissolvedin 800 ml of diethylene glycol and the solution is stirred with 1050 mlof hydrazine hydrate for 48 h at a bath temperature of about 140° C. Thecooled mixture is poured into 4.5 l of ether and 4.5 l of water and theorganic phase is extracted twice with 2.3 l of dichloromethane eachtime. The combined organic phases are dried with sodium sulphate andevaporated in vacuo. 784 g of solvent-containing crude product areobtained, which is reacted further without working up.

[0239] R_(f)=0.37 (dichloromethane:methanol=10:1)

[0240]¹H-NMR (d₆-DMSO, 250 MHz, TMS): δ=2.13 (S, 3H), 2.22 (S, 3H), 4.02(S, 2H), 6.26 (S, 1H), 6.35 (S, 1H), 7.11 (S, 1H) ppm.

Example V

[0241] 2-Hydrazino-4-picoline (2-hydrazino-4-methylpyridine)

[0242] In analogy to the procedure of Example IV, 2-hydrazino-4-picolineis prepared from 2-chloro-4-picoline.

[0243] R_(f)=0.06 (dichloromethane:methanol=10:1)

Example VI

[0244] 2,4-Dimethyl-5,6,7,8-tetrahydro-α-carboline

[0245] 78 g (at most 0.49 mol) of crude compound from Example IV arereacted with 59 ml (0.56 mol) of cyclohexanone at room temperature(about 25° C.), whereon the internal temperature rises. After 2 h, thestarting material has disappeared (TLC checking;dichloromethane:methanol=10:1). The mixture is taken up in 40 ml ofdiethylene glycol and reacted under reflux, constituents having aboiling point lower than the solvent (e.g. water of reaction and excesscyclohexanone) being removed by distillation (water separator). After 3h, the intermediate hydrazone has disappeared (TLC checking, petroleumether:ethyl acetate=1:1); the reaction mixture is cooled to roomtemperature and stirred with acetone. The precipitate obtained isfiltered off with suction, washed with acetone and dried in vacuo (34.4g). The largely solvent-free mother liquors are again treated withacetone, a further 9.3 g of product being obtained (total yield overthree stages: 43.7 g/0.22 mol/47%).

[0246] M.p.: 248° C. (uncorrected)

[0247] R_(f)=0.41 (dichloromethane:methanol=20:1)

[0248]¹H-NMR (d₆-DMSO, 200 MHz, TMS): δ=1.78 (M, 4H), 2.40 (S, 3H), 2.48(S, 3H), 2.64 (M, 2H), 2.82 (M, 2H), 6.57 (S, 1H), 10.84 (S, 1H) ppm.

[0249] The compounds of Table I are prepared analogously to theprocedure of Example VI. TABLE I Starting R_(f) material Ex. No.(solvent) (hydrazine*) VII

0.59 (A) Ex. No. IV VIII

0.36 (E) Ex. No. IV IX

0.45 (G) X

0.46 (E) XI

0.06 (L) XII

0.41 (E) XIII

0.40 (E) XIV

0.59 (O) XV

0.34 (E) XVI

0.42 (E) XVII

0.59 (G) XVIII

0.85 (G)

Example XIX

[0250] 2,4-Dimethyl-α-carboline

[0251] 100 g (499 mmol) of the compound from Example VI are reactedunder reflux with 164 ml (1 mol) of diethyl fumarate on 52 g ofpalladium (5% on carbon) in 700 ml of diethylene glycol. A small amountof ethanol distils off at the high internal temperature (if desired usea water separator). After about 8 h, the starting material hasdisappeared (TLC checking, petroleum ether:ethyl acetate=1:1, detectionin an iodine chamber). The cooled mixture is treated with 3 l ofacetone, boiled, filtered off hot with suction through a clarifyingfilter (Seitz) and washed with 1 l of hot acetone. On cooling aprecipitate is obtained which yields 58.3 g of product after filteringwith suction, rinsing with cold acetone and drying in vacuo. The motherliquor is largely freed from acetone in vacuo, the precipitate which isdeposited being worked up as above (9.4 g). The filtrate is again freedfrom acetone; after addition of n-pentane, product precipitates afurther time (3.1 g/working up see above); total yield 72%.

[0252] M.p. 220-221° C. (uncorrected)

[0253] R_(f)=0.47 (petroleum ether:ethyl acetate=1:1)

[0254]¹H-NMR (d₆-DMSO, 200 MHz, TMS): δ=2.54 (S, 3H), 2.75 (S, 3H), 6.89(S, 1H), 7.20 (M, 1H), 7.40 (M, 1H), 7.48 (DD, 1H), 8.05 (DD, 1H), 11.61(S, 1H) ppm.

Example XX

[0255] tert-Butyl 4-methylphenyl-acetate

[0256] 450 g (3 mol) of 4-methylphenyl-acetic acid (Aldrich), 1.13 l (12mol) of tert-butanol and 90 g (0.74 mol) of4-(N,N-dimethylamino)pyridine are dissolved in 2 l of dichloromethane.After addition of 680 g (3.3 mol of dicyclohexylcarbodiimide, dissolvedin 400 ml of dichloromethane, the mixture is stirred at 25° C. for 20 h,the precipitated urea is filtered off with suction and flashed with 200ml of dichloromethane, and the organic phase is washed twice each with500 ml of 2 M hydrochloric acid and water. The organic phase isconcentrated and distilled.

[0257] Yield: 408 g (66% of theory)

[0258] Boiling point: 73-78° C./0.2 mm

Example XXI

[0259] tert-Butyl 2-Cyclopentyl-2-(4-methylphenyl)acetate

[0260] 33.5 g, (0.3 mol of potassium tert-butoxide are initiallyintroduced into 100 ml of anhydrous DMF at 0° C., and 51.6 g (0.25 mol)of the compound from Example XX in 250 ml of anhydrous DMF are addeddropwise. The mixture is stirred at 0° C. for 30 min and 32.2 ml (0.3mol) of cyclopentyl bromide in 150 ml of anhydrous DMF are addeddropwise at 5-15° C. and the mixture is stirred at 25° C. for 20 h.After concentrating, the residue is partitioned between water anddiethyl ether, and the ether phase is dried over sodium sulphate andconcentrated. The product crystallizes out.

[0261] Yield: 67 g (97.5% of theory)

[0262] Solidification point: 51-53° C.

[0263] The compounds of Table II are prepared in analogy to theprocedure of Example XXI: TABLE IL

Ex. No. D R¹⁹ R_(f) (solvent) Starting material* XXII cHex tBu 0.71 (I)Ex. No. XX XXIII cHept tBu 0.32 (I) Ex. No. XX XXIV iPr CH₃ 0.86 (Q)sigma XXV iBu tBu 0.84 (R) Ex. No. XX XXVI cPent CH₃ 0.59 (H) sigmaXXVII cHept CH₃ 0.57 (I) sigma

Example XXVIII

[0264] tert-Butyl 2-(4-bromomethyl-phenyl)-2-cyclopentyl-acetate

[0265] 27.4 g (0.1 mol) of the compound from Example XXI are dissolvedin 200 ml of tetrachloromethane and the solution is heated to boiling.After addition of 0.82 g of azobisisobutyronitrile, 18.7 g (0.105 mol)of N-bromosuccinimide are added in portions and the mixture is thenrefluxed for 1 h, cooled to 0° C. and succinimide is filtered off. Afterconcentrating the filtrate the product precipitates. It is washed withpetroleum ether (40/60) and dried.

[0266] Yield: 20 g (57% of theory)

[0267] M.p.: 73-76° C.

[0268] The compounds of Table III are prepared analogously to theprocedure of Example XXVIII: TABLE III

Starting material* Ex. No. D R¹⁹ R_(f) (solvent) (Syn. from Ex. No.)XXIX cHex tBu 0.58 (H) Ex. No. XXIII XXX cHept tBu 0.84 (M) Ex. No.XXIII XXXI iPr CH₃ 0.78 (M) Ex. No. XXIV XXXII iBu tBu 0.86 (M) Ex. No.XXV XXXIII cPent CH₃ 0.63 (H) Ex No. XXVI XXXIV cHept CH₃ 0.59 (I) ExNo. XXVII

Example XXXV

[0269] tert-Butyl2(R,S)-2-cyclopentyl-2-[4-(2,4-dimethyl-α-carbolin-9-yl)-methyl]phenyl-acetate

[0270] 73.6 g (375 mmol) of the compound from Example XIX are reacted at25° C. for 30 min with 42.13 g (375 mmol) of potassium tert-butoxide in700 ml of anhydrous N,N-dimethylformamide and the mixture is thentreated with 161.7 g (375 mmol) of the compound from Example XXVIII,dissolved in 680 ml of anhydrous N,N-dimethylformamide. The reaction iscomplete after 1 h (TLC checking; petroleum ether:ethyl acetate=10:1).For working up, 2 l of buffer solution (pH=4/Merck) and 2 l of water areadded, the precipitate which is deposited is filtered off, washed withwater and again filtered off rapidly. The moderately damp solid is thenstirred successively with petroleum ether and methanol and filtered offwith suction. Vacuum drying over phosphorus pentoxide yields 139.8 g(298 mmol/79%) of product.

[0271] M.p.: 160-161° C. (uncorrected).

[0272] R_(f)=0.39 (petroleum ether:ethyl acetate=10:1)

[0273]¹H-NMR (CDCl₃, 250 MHz, TMS): δ=0.91 (M, 1H), 1.18-1.68 (M, 6H),1.87 (M, 1H), 1.47 (S, 9H), 2.42 (M, 1H), 2.66 (S, 3H), 2.83 (S, 3H),3.09 (D, 1H), 5.67 (S, 2H), 6.88 (S, 1H), 7.13-7.41 (M, 7H), 8.09 (D,1H) ppm.

[0274] The compounds of Tables IV and V are prepared analogously to theprocedure of Example XXXV: TABLE IV

R_(f) Starting material Ex. No. Z D (solvent) (Syn. from Ex. No.) XXXVI

cPent 0.28 (H) Benzyl bromide: Ex. No. XXVII Heterocycle: Ex. No. VIXXXVII

cHept 0.47 (H) Benzyl bromide: Ex. No. XXX Heterocycle: Ex. No. XIXXXVIII

cHept 0.54 (L) Benzyl bromide: Ex. No. XXX Heterocycle: Ex. No. VIIXXXIX

cHept 0.27 (H) Benzyl bromide: Ex. No. XXX Heterocycle: Ex. No. VI XL

cPent 0.59 (D) Benzyl bromide: Ex. No. XXVIII Heterocycle: Ex. No. VIIIXLI

cHept 0.29 (H) Benzyl bromide: Ex. No. XXX Heterocycle: Ex. No. VIIIXLII

cPent 0.70 (M) Benzyl bromide: Ex. No. XXVIII Heterocycle: Ex. No. IXXLIII

cHept 0.36 (H) Benzyl bromide: Ex. No. XXX Heterocycle: Ex. No. IX XLIV

cHept 0.48 (L) Benzyl bromide: Ex. No. XXX XLV

cPent 0.49 (C) Benzyl bromide: Ex. No. XXVIII XLVI

cPent 0.51 (C) Benzyl bromide: Ex. No. XXVIII XLVII

cPent 0.54 (C) Benzyl bromide: Ex. No. XXVIII XLVIII

cPent 0.37 (N) Benzyl bromide: Ex. No. XXVIII Heterocycle: Ex. No. XI IL

cHept 0.56 (H) Benzyl bromide: Ex. No. XXX Heterocycle: Ex. No. XI L

cPent 0.57 (C) Benzyl bromide: Ex. No. XXVIII LI

cHex 0.35 (H) Benzyl bromide: Ex. No. XXIX Heterocycle: Ex. No. VI LII

cHex 0.57 (B) Benzyl bromide: Ex. No. XXIX Heterocycle: Ex. No. XIX LIII

cPent M.p. =189-190° C. Benzyl bromide: Ex. No. XXVIII Heterocycle: a)C. Herdeis et al., Heterocycles 22, 2277 (1984). LIV

iBu 0.49 (M) M.p.: 142° C. MS (CI/NH₃) 457 (100%) Benzyl bromide: c) Ex.No. XXXII Heterocycle: c) Ex. No. XIX

[0275] TABLE V

R_(f) (solvent Starting material Ex. No. Z D MS/M.p. (Syn. from Ex. No.)LV

iPr 0.39 (M) M.p. = 159° C. MS (Cl/NH₃): 401 (100%) Benzyl bromide: Ex.No. XXXI Heterocycle: Ex. No. XIX LVI

cPent 0.76 (B) Benzyl bromide: Ex. No. XXXIII Heterocycle: Ex. No. XIXLVII

cHept 0.26 (H) Benzyl bromide: Ex. No. XXXIV Heterocycle: Ex. No. VILVIII

cHept 0.64 (K) Benzyl bromide: Ex. No. XXXIV LIX

cHept 0.29 (H) Benzyl bromide: Ex. No. XXXIV Heterocycle: Ex. No. X LX

cHept 0.30 (H) Benzyl bromide: Ex. No. XXXIV Heterocycle: Ex. No. XIX

Example LXI

[0276]2-(R,S)-2-Cyclopentyl-2-[4-(2,4-dimethyl-α-carbolin-9-yl)-methyl]phenyl-aceticacid hydrochloride

[0277] 139.8 g (298 mmol) of the compound from Example XXXV aredissolved in 1 l of 1,4-dioxane and the solution is stirred at 70° C.for 3 h with 240 ml of concentrated hydrochloric acid (37% strength).After reaction is complete (TLC checking, petroleum ether: ethylacetate=10:1), the mixture is cooled to about 15° C. and then poured inportions into 5 l of water. The pH is adjusted to 2.8 using 2 M aqueoussodium hydroxide solution, and the precipitate obtained is filtered offwith suction through a paper filter and washed with water until thewashing water has a pH>4. The rapidly filtered off solid is stirred with1 l of petroleum ether (boiling range 60-80° C.), filtered off withsuction again and dried over phosphorus pentoxide in vacuo.

[0278] Yield: 130.3 g (290 mmol/97%)

[0279] M.p.: 260-262° C. (uncorrected)

[0280] R_(f)=0.51 (dichloromethane:ethanol=20:1)

[0281]¹H-NMR (d₆-DMSO, 200 MHz, TMS): δ=0.88 (M, 1H), 1.09-1.67 (M, 6H),1.79 (M, 1H), 2.38 (M, 1H), 2.68 (S, 3H), 2.84 (S, 3H), 3.16 (D, 1H),4.7-5.9 (1H), 5.80 (S, 2H), 7.12-7.26 (M, 5H), 7.32 (M, 1H), 7.49 (M,1H), 7.59 (D, 1H), 8.17 (D, 1H) ppm.

[0282] The compounds of Table VI are prepared analogously to theprocedure of Example LXI: TABLE VI

R_(f) Starting material Ex. No. Z D (solvent) (Syn. from Ex. No.) LXII

cPent 0.37 (A) Ex. No. XXXVI LXIII

cHept 0.23 (G) Ex. No. XXXVII LXIV

cHept 0.30 (E) Ex. No. XXXVIII LXV

cHept 0.27 (D) Ex. No. XXXIX LXVI

cPent 0.37 (C) Ex. No. XL LXVII

cHept 0.15 (C) Ex. No. XLI LXVIII

cPent 0.43 (A) Ex. No. XLII LXIX

cHept 0.27 (C) Ex. No. XLIII LXX

cHept 0.17 (E) Ex. No. XLIV LXXI

cPent 0.07 (C) Ex. No. XLV LXXII

cPent 0.26 (C) Ex. No. XLVI LXXIII

cPent 0.39 (C) Ex. No. XLVII LXXIV

cPent 0.46 (C) Ex. No. XLVIII LXXV

cHept 0.68 (E) Ex. No. IL LXXVI

cPent 0.44 (C) Ex. No. L LXXVII

cHex 0.44 (C) Ex. No. LI LXXVIII

cHex 0.55 (C) Ex. No. LII LXXIX

cPent M.p. =204-205° C. Ex. No. LIII LXXX

iBu 0.36 (A) M.p.: 156° C. MS(FAB): 401 (100%) 154 (90%) Ex. No. LIV

Example LXXXI

[0283]2-(R,S)-2-[4-(2-Methyl-5,6,7,8-tetrahydro-α-carbolin-9-yl)-methyl-phenyl]-2-cylcoheptyl-aceticacid

[0284] 1.5 g (3.37 mmol) of the compound from Example LIX are reactedwith 20 ml of 1 M methanolic sodium hydroxide solution for 48 h. Wateris added thereto and the methanol component is evaporated. The alkalineaqueous phase is extracted several times with ether, freed from residuesof organic solvent in vacuo and adjusted to a pH of about 2 at 0-5° C.using aqueous 1 M hydrochloric acid. The precipitate which is depositedin this process is filtered off with suction, thoroughly washed withwater and dried over phosphorus pentoxide in a high vacuum.

[0285] Yield: 1.18 g

[0286] The reaction can be accelerated using potassium hydroxide insteadof sodium hydroxide and with addition of 1, 4, 7, 10, 13,16-hexaoxacyclooctadecane.

[0287] R_(f)=0.39 (petroleum ether:ethyl acetate=2:1)

[0288] The compounds of Table VII are prepared in analogy to theprocedure of Example LXXXI: TABLE VII

Starting R_(f) material (solvent) (Synthesis Ex. No. Z D I MS/M.p. fromEx. No.) LXXXII Method 1

iPr rac 0.28 (A) M.p. = 225° C. MS(FAB): 387 (100%) 154 (80%) Ex. No. LVLXXXIII

cHept rac 0.05 (L) Ex. No. LVII LXXXIV

cHept rac 0.11 (K) Ex. No. LVIII LXXXVI

cHept rac 0.23 (G) Ex. No. LX LXXXVI

cPent rac 0.51 (C) Ex. No. LVI

[0289] Example LXXXII can also be prepared by method 2 which follows:

[0290]2-[4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-(prop-2-yl)aceticacid

[0291] 1.11 g (2.77 mmol) of the compound from Example No. LV are boiledunder reflux for 18 hours in 45 ml of methanol and 3 ml of 2 M aqueoussodium hydroxide solution. As the reaction is incomplete according toTLC (dichloromethane:methanol=20:1), 30 ml of tetrahydrofuran and afurther 3 ml of 2 M aqueous sodium hydroxide solution are added, a clearsolution being obtained. After boiling under reflux for four hours, thereaction is complete (TLC, see above). The mixture is cooled, dilutedwith water and neutralized with 2 M aqueous hydrochloric acid. Theprecipitate which is obtained in this process is filtered off withsuction, washed with water and dried over phosphorus pentoxide in vacuo.

[0292] Yield: 0.597 g

[0293] M.p.=225° C.

[0294] R_(f)=0.28 (dichloromethane:methanol=20:1)

[0295] The compounds of Table VIII are prepared analogously to theprocedure of Example XXXV: TABLE VIII

Ex. No. -Z M.p. (° C.) Starting material* LXXXVII

164-165 LXXXVIII

201-202

[0296] The compounds of Table IX are prepared analogously to theprocedure of Example LXI: TABLE IX

Starting material from Ex. No. -Z M.p. (° C.) Ex. No. LXXXIX

262-263 LXXXVII XC

279-280 LXXXVIII

Example XCI

[0297] 2-Hydrazino-5-trifluoromethylpyridine

[0298] In analogy to the procedure of Example No. IV,2-hydrazino-5-trifluoromethylpyridine is prepared from2-chloro-5-trifluoromethylpyridine.

[0299] R_(f)=0.37 (BABA)

Example XCII

[0300] 5-Oxo-5,6,7-tetrahydro-α-carboline

[0301] 3.3 g (19.2 mmol) of 5,6,7,8-tetrahydro-α-carboline (Lit.: S.Okuda and M. M. Robinson, J. Am. Chem. Soc. 81, 740 (1959)) areinitially introduced into 43 ml of tetrahydrofuran while stirring at 0°C. and the mixture is treated dropwise with a solution of 15.5 g (68.2mmol) of DDQ in 277 ml of tetrahydrofuran and 31 ml of water. Thereaction mixture is stirred at 0° C. for 5 minutes and at 20° C. for 2hours, then treated with a buffer of pH=10 (Merck) and extracted withdiethyl ether. The evaporated organic phase yields a crude product whichis purified by chromatography (silica gel 60, Merck, first petroleumether:ethyl acetate=1:1, then dichloromethane:methanol=20:1). Thefractions thus obtained are precipitated by stirring with acetone, andthe product is filtered off with suction and freed from the solvent invacuo.

[0302] Yield: 0.92 g

[0303] R_(f)=0.17 (petroleum ether:ethyl acetate=1:4).

[0304] The compounds of Table X are prepared analogously to theprocedure of Example VI: TABLE X M.p. (° C.) Starting material Ex. No.-Z- R_(f (solvent)) MS (EI) from Ex. No. XCIII

0.27 (E) V XCIV

0.46 (G) 240 (52%) 212 (100%) XCI

[0305] The compounds of Table XI are prepared analogously to theprocedure of Example XIX: TABLE XI M.p. (° C.) Starting material Ex. No.-Z- R_(r) (solvent) MS (EI) from Ex. No. XCV

0.39 (G) 250 (100%) IX XCVI

0.45 (G) X XCVII

0.48 (G) 236 (100%) XCIV XCVIII

0.3 (E) XCIII

[0306] The compounds of Table XII are prepared analogously to theprocedure of Example XXXV: TABLE XII

M.p. [° C.] Starting material Ex. No. Z D R_(r) (solvent) from Ex. No.IC

cPent 0.73 (C) Benzoyl bromide: Ex. No. XXVIII C

cPent 0.63 (H) Benzoyl bromide: Ex. No. XXVIII Heterocycle: Ex. No. XCVCI

cPent 0.27 (H) Benzoyl bromide: Ex. No. XXVIII Heterocycle: Ex. No. XCVICII

cPent 0.33 (H) Benzoyl bromide: Ex. No. XXVIII Heterocycle; Ex. No. XCICIII

cPent 0.41 (H) Benzoyl bromide: Ex. No. XXVIII Heterocycle: Ex. No.XCVII CIV

cPent 0.18 (H) Benzoyl bromide: Ex. No. XXVIII Heterocycle: Ex. No.XCVIII

[0307] The compounds of Table XIII are prepared analogously to theprocedure of Example LXI: TABLE XIII

M.p. Starting [° C.] material Ex. R_(r) (sol- from No. Z D vent) Ex. No.CV

cPent 0.27 (C) IC CVI

cPent 0.49 (C) C CVII

cPent 0.38 (C) CI CVIII

cPent 0.35 (C) CII CIX

cPent 0.43 (C) CIII CX

cPent 0.29 (C) CIV

Example No. CXI

[0308] 1-(R,S)-1-Phenyl-2-triphenylmethyloxy-ethanol

[0309] 13 g (94 mmol) of 1-(R,S)-1-Phenyl-2-hydroxy-ethanol are reactedat 20° C. with 15.6 ml (113 mmol) of triethylamine and 23.6 g (84.6mmol) of triphenylmethyl chloride in 200 ml of DMF. After 20 h, themixture is poured into buffer of pH=4 (Merck), the phases are separated,and the organic phase is dried with magnesium sulphate and evaporated todryness. The crude product is purified by chromatography on silica gel60 (Merck/petroleum ether:ethyl acetate=20:1 later 10:1);

[0310] yield 27 g.

[0311] R_(f)=0.36 (petroleum ether:ethyl acetate=5:1)

Example No. CXII

[0312] 6-Chloro-5-methyl-3-nitro-2-(2-oxo-cyclohexyl)-pyridine

[0313] 20 g (95.7 mmol) of 2,6-dichloro-5-methyl-3-nitro-pyridine arereacted with 13.3 ml (95.7 mmol) of triethylamine and 14.5 g (95.7 mmol)of freshly distilled 1-pyrrolidino-cyclopentene at 20° C. in 200 ml ofDMF under argon as a protective gas. After the starting material hasdisappeared according to thin-layer chromatography (silica gel/petroleumether:ethyl acetate=4:1), 200 ml of 1 M hydrochloric acid are added andthe mixture is diluted with about 600 ml of water. The precipitate whichis deposited is filtered off with suction, dried over phosphoruspentoxide in a high vacuum and purified by chromatography (silica gel60/Merck/petroleum ether:ethyl acetate=2:1).

[0314] R_(f)=0.69 (petroleum ether:ethyl acetate=4:1)

Example No. CXIII

[0315] 2-Methyl-5,6,7,8-tetrahydro-δ-carboline

[0316] 2.8 g (10.4 mmol) of the compound from Example CXII are reactedon 0.5 g of palladium (5%)/carbon in 30 ml of THF under a hydrogenpressure of 3 bar for 18 h. The catalyst is then filtered off withsuction and washed several times with methanol and dichloromethane. Thefiltrate is evaporated and dried in a high vacuum;

[0317] yield: 2.1 g

[0318] R_(f)=0.53 (dichloromethane:ethanol=5:1)

Example No. CXIV

[0319] 3-Methyl-5,6,7,8-tetrahydro-α-carboline hydrochloride

[0320] 13.0 g (120.2 mmol) of 2-amino-5-methyl-pyridine are dissolved in150 ml of ethanol and the solution is stirred with 60 ml of 2 Mhydrochloric acid, evaporated to dryness and finally dried over sodiumhydroxide and phosphorus pentoxide in a high vacuum. The product thusobtained is boiled under reflux in a water separator with 2.2 g (20.1mmol) of 2-amino-5-methyl-pyridine and 11.4 g (50.0 mmol) of2-hydroxy-cyclohexanone dimer in 120 ml of 1,2-dichlorobenzene for 6 h,11.4 g (50.0 mmol) of 2-hydroxy-cyclohexanone dimer are then added againand the mixture is boiled under reflux for a further 3 h. On cooling, aprecipitate is deposited at 20° C. 150 ml of acetone are added, themixture is cooled to 0° to 5° C. with stirring, and the precipitate isfiltered off with suction and washed with cold ether. The productobtained is dried over phosphorus pentoxide in a high vacuum; yield 18g.

[0321] R_(f)=0.29 (dichloromethane:ethanol=20:1)

[0322] The compounds of the following Table XIV are obtained in analogyto the procedure of Example No. XIX: TABLE XIV R_(r) (sol- Starting Ex.No. Heterocycle vent) material CXV

0.16 (C) CXVI

0.37 (C) Ex. No. CXIII CXVII

0.17 (D) Ex. No. CXIV

Example No. CXVIII

[0323] 1-Chloro-5,7-dimethyl-β-carboline

[0324] 10.2 g (49 mmol) of the compound from Example No. CXV are reactedat 125° C. for 24 h with 222 ml (2.4 mol) of phosphorus oxychloride and155 μl of N,N-dimethyl-aniline. The mixture is poured into 1 l of icewater after cooling, then neutralized with aqueous sodium carbonatesolution and extracted several times with ethyl acetate. The organicphase is dried with magnesium sulphate, evaporated and freed from theresidual solvent in a high vacuum. The crude product is purified bychromatography on silica gel 60 (Merck/dichloromethane);

[0325] yield: 4.3 g.

[0326] R_(f)=0.39 (dichloromethane:ethanol=20:1)

Example No. CXIX

[0327] 5,7-Dimethyl-β-carboline

[0328] 3.8 g (16.5 mmol) of the compound from Example CXVIII are reactedwith 1.3 g of sodium hydrogen carbonate on 700 mg of palladium(10%)/carbon at a hydrogen pressure of about 3 bar and 20° C. for 10 din 40 ml of THF, 300 mg of palladium (10%)/carbon and 5 ml of methanolbeing added on every second day. The catalyst is then filtered off withsuction through kieselguhr, washed with THF, boiled in methanol anddichloromethane and again filtered off with suction. The combinedorganic solutions are evaporated, and the residue is precipitated bystirring with ether and filtered off with suction. After vacuum drying,3 g of product are obtained.

[0329] R_(f)=0.13 (dichloromethane:ethanol=20:1)

Example No. CXX

[0330] 5,6-Dimethyl-1-(pyrid-2-yl)-1H-benzotriazole

[0331] 14.85 g (103 mmol) of 5,6-dimethyl-1H-benzotriazole are dissolvedin 150 ml of anhydrous DMSO, reacted with 5 g (104 mmol) of 50% strengthsodium hydride (+40% paraffin oil) at 20° C. until evolution of hydrogenis complete, treated with 10 g (103 mmol) of 2-fluoro-pyridine and themixture is boiled under reflux for 18 h. After cooling to 20° C., themixture is made up to a volume of about 1 l with water, and theresulting precipitate is filtered off with suction and washed withwater. The substance, which is dried over phosphorus pentoxide in a highvacuum, is purified by chromatography on silica gel 60(Merck/dichloromethane to dichloromethane:ethanol =100:1);

[0332] yield: 10.6 g.

[0333] R_(f)=0.38 (dichloromethane:ethanol=50:1)

Example No. CXXI

[0334] 6,7-Dimethyl-α-carboline

[0335] 8.9 g (39.7 mmol) of the compound from Example No. CXX are slowlyheated to 165° C. in 140 g of polyphosphoric acid under argon, themixture being poured into 1.5 l of water and adjusted to pH=67 with 1 Maqueous sodium hydroxide solution before disappearance of the startingmaterial (TLC checking/dichloromethane:ethanol =20:1). The precipitateobtained is filtered off with suction, washed with water, rapidlyfiltered off with suction, then washed with petroleum ether and filteredoff with suction again. After vacuum drying, 1.8 g of product areobtained.

[0336] R_(f)=0.32 (dichloromethane:ethanol=20:1)

[0337] The compounds in Table XV are prepared in analogy to theprocedure of Example No. XXI: TABLE XV Ex. No. R_(r) (solvent) CXXII

0.56 (H) CXXIII

CXXIV

[0338] The compounds in Table XVI are prepared in analogy to theprocedure of Example No. XXVIII: TABLE XVI Starting R_(r) material Ex.No. (solvent) (Ex. No.) CXXV

0.40 (H) CXXII CXXVI

CXXIII CXXVII

CXXIV

[0339] The compounds in Table XVII are prepared in analogously to theprocedure of Example No. XXXV: TABLE XVII

Position Starting material Ex. No. Z (o, m or p) {circle over (1)} D R¹⁰R_(r) (solvent) MS Ex. No. CXXVIII

p — H Me 0.59 (G) DCI: 359 (100%) XIX CXXIX

p rac cPent Me 0.51 (D) XXXIII CXXX

p rac cPent Me 0.22 (C) XXXIII (Harman is commercially available fromAldrich). CXXXI

m rac cPent Me 0.55 (D) XIX and CXXV CXXXII

p rac cPent Me 0.21 (D) CXVI and XXXIII CXXXIII

p rac cPent tBu XXVIII and CXXI CXXXIV

p rac cPent tBu XXVIII and CXXVII CXXXV

p rac cPent tBu XXVIII and CXIX CXXXVI

p rac cPent Me 0.13 (L) XXXIII CXXXVII

p rac Me tBu 0.43 (L) XIX CXXXVIII

p rac Et tBu 0.51 (L) XIX CXXXIX

p rac nPent Et XIX and CXXVII CXL

p rac

Et XIX and CXXVI

[0340] The compounds in Table XXVIII are prepared in analogously to theprocedure of Example Nos. LXI or LXXXI: TABLE XVIII

Preparation Position Starting material analogous to Ex. No. Z (o, m orp) {circle over (1)} D R_(r) (solvent) MS Ex. No. Ex. No. CXLI

p — H 0.56 (O) CXXVIII LXXXI CXLII

p rac cPent 0.14 (G) CXXIX LXXXI CXLIII

p rac cPent 0.50 (U) CXXX LXXXI CXLIV

m rac cPent 0.14 (D) CXXXI LXXXI CVL

p rac cPent 0.10 (D) CXXXII LXXXI CVLI

p rac cPent 0.34 (C) CXXXIII LXI CVLII

p rac cPent CXXXIV LXI CVLIII

p rac cPent 0.15 (C) CXXXV LXI CIL

p rac cPent CXXXVI LXXXI CL

p rac Et CXXXVIII LXI CLI

p rac Me CXXXVII LXI CLII

p rac nPent CXXXIX LXXXI CLIII

p rac

CXL LXXXI

PREPARATIONS EXAMPLES Examples 1, 2 and 3

[0341] 2—S— and2-(R)-2-[4-(2,4Dimethyl-5,6,7,8-tetrahydro-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-aceticacid N—[(R)-phenylglycinolamide]

[0342] 3.00 g (7.2 mmol of the compound from Example LXII are dissolvedin 70 ml of dichloromethane with 0.99 g (7.2 mmol) of (R)-phenylglycinol(Aldrich), and the solution is treated successively at 0° C. with 1.07 g(7.9 mmol) of 1-hydroxy-1H-benzotriazole hydrate (Aldrich), 1.58 g (8.3mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride(Aldrich) and 2 ml of triethylamine and then stirred at room temperaturefor 20 hours. The organic solution is extracted with aqueous ammoniumchloride solution, with aqueous sodium hydrogen carbonate solution andwith a buffer of pH=4 (ready-to-use buffer solution, E. Merck,Darmstadt), dried with solid anhydrous sodium sulphate and evaporated.

[0343] Yield of the diastereomer mixture: 3.50 g (Example 1).

[0344] The product mixture is separated by chromatography (silica gel,dichloromethane: ethanol=50:1):

Example No. 2

[0345] Diastereomer A [2(S)-diastereomer]: 1.23 g

[0346] R_(f)=0.18 (dichloromethane:ethanol=50:1)

[0347]¹H-NMR (d-DMSO, 250 MHz, TMS): δ=0.87 (M, 1H), 1.19-1.63 (M, 6H),1.72 (M, 1H), 2.45 (M, 1H), 2.58 (S, 3H), 2.79 (S, 3H), 3.26 (D, 1H),3.44-3.53 (M, 2H), 4.21-4.31 (M, 2H), 5.63 (S, 2H), 6.97-7.11 (M, 8H),7.20-7.28 (M, 3H), 7.41 (M, 1H), 7.54 (D, 1H), 8.12 (D, 1H), 8.24 (D,1H) ppm.

Example No.3

[0348] Diastereomer B [2(R)-diastereomer]: 1.12 g

[0349] R_(f)=0.16 (dichloromethane:ethanol=50:1) ¹H-NMR (d-DMSO, 250MHz, TMS): δ=0.84 (M, 1H), 1.07-1.59 (M, 7H), 2.34 (M, 1H), 2.61 (S,3H), 2.80 (S, 3H), 3.25 (D, 1H), 3.43 (M, 2H), 4.63-4.72 (M, 2H), 5.66(S, 2H), 6.98 (S, 1H), 7.13 (M, 2H), 7.20-7.30 (M, 8H), 7.43 (M, 1H),7.57 (D, 1H), 8.12 (D, 1H), 8.36 (D, 1H) ppm.

[0350] The absolute configurations of the enantiomerically purecarboxylic acids 2-(S)— and2-(R)-2-{4[(quinolin-2-yl)-methoxy]phenyl}-2-cyclopentyl-acetic acid[cf. EP 509 359] are known, so the absolute configurations of the amidesEx. No. C1 and Ex No. C2 prepared therefrom analogously to the procedureof Examples 1 and 2 can be derived. The ¹H-NMR spectra of the twodiastereomeric products (200 MHz, d₆-DMSO, TMS for Example No. C1 and250 MHz, d₆-DMSO, TMS for Example No. C2/FIG. 1) have significantdifferences in the aromatic region: the H signals of the phenyl radicalof Ex No. C1 are at about 7.1 ppm (3H) and 7.3 ppm (2H) and the Hsignals of Ex. No. C2 are at about 7.3 ppm (5H). This finding isapplicable to the compounds of Examples 2 and 3 (FIG. 2) and also tomany other derivatives of this type.

[0351] The examples mentioned in Tables 1, 2 and 3 are prepared inanalogy to the procedure of Examples 1, 2 and 3: TABLE 1

R_(r) Starting material Ex. No. Z D 1 (solvent) *(Ex. No.) 4

cPent rac 0.41/0.46 (E) LXI 5

cPent S 0.46 (E) LXI 6

cPent R 0.41 (E) LXI 7

cHept rac 0.26/0.29 (D) LXIII 8

cHept S 0.29 (D) LXIII 9

cHept R 0.26 (D) LXIII 10

cHept rac 0.20/0.24 (E) LXIV 11

cHept S 0.24 (E) LXIV 12

cHept R 0.20 (E) LXIV 13

cHept rac 0.35 (C) LXV 14

cHept S 0.35 (C) LXV 15

cHept R 0.35 (C) LXV 16

cPent rac 0.33/0.37 (C) LXVI 17

cHept rac 0.25/0.38 (C) LXVII 18

cHept S 0.38 (C) LXVII 19

cHept R 0.25 (C) LXVII 20

cPent rac 0.29 (A) LXVIII 21

cHept rac 0.23/0.28 (D) LXIX 22

cHept S 0.28 (D) LXIX 23

cHept R 0.23 (D) LXIX 24

cHept rac 0.10/0.18 (E) LXX 25

cHept S 0.18 (E) LXX 26

cHept R 0.10 (E) LXX 27

cHept rac 0.17/0.23 (B) LXXXI 28

cHept rac 0.12/0.15 (B) LXXXIV 29

cPent rac 0.28 (E) LXXI 30

cPent rac 0.29 (C) LXXII 31

cPent rac 0.24 (C) LXXIII 32

cPent rac 0.39/0.48 (C) LXXIV 33

cPent S 0.48 (C) LXXIV 34

cPent R 0.39 (C) LXXIV 35

cHept rac 0.23/0.29 (D) LXXV 36

cPent rac 0.26 (A) LXXVI 37

cHex rac 0.28/0.30 (D) LXXVII 38

cHex rac 0.21/0.23 (D) LXXVIII

[0352] TABLE 2

Starting Ex. R_(r) material No. 1 (solvent) *(Ex. No.) 39

rac 0.42 (C) LXI 40

R 0.42 (C) LXI 41

S 0.42 (C) LXI

[0353] TABLE 3

Ex. R_(f) Starting material No. Z D X 1 (solvent) (Ex. No.) 42

cHept H rac 0.39 (C) Carboxylic acid: Ex. No. LXIII Amine from Aldrich43

cHept H rac 0.78 (E) Carboxylic acid: Ex. No. LXIV Amine from Aldrich 44

cPent H rac 0.34 (D) Carboxylic acid: Ex. No. LXII Amine from Aldrich 45

cPent H (−)-ent* 0.34 (D) Carboxylic acid: Ex. No. LXII Amine fromAldrich 46

cPent H (+)-ent* 0.34 (D) Carboxylic acid: Ex. No. LXII Amine fromAldrich 47

cHept H rac 0.25 (C) Carboxylic acid: Ex. No. LXV Amine from Aldrich 48

cHept H rac 0.42 (C) Carboxylic acid: Ex. No. LXVII Amine from Aldrich49

cHept H rac 0.45 (C) Carboxylic acid: Ex. No. LXIX Amine from Aldrich 50

cHept H rac 0.71 (E) Carboxylic acid: Ex. No. LXX Amine from Aldrich 51

cHept H rac 0.59 (B) Carboxylic acid: Ex. No. LXXXI Amine from Aldrich52

cHept H rac 0.40 (B) Carboxylic acid: Ex. No. LXXXIV Amine from Aldrich53

cHept 3-OH rac 0.45 (D) Carboxylic acid: Ex. No. LXV Amine: Ref.: US 4388 250 54

cHept 4-OH rac 0.39 (A) Carboxylic acid: Ex. No. LXV Amine: Ref.: C.Hartmann and J. P. Klinman, Biochemistry, 30, 4605 (1991) 55

cHept 2-OCH₃ rac 0.15 (B) Carboxylic acid: Ex. No. LXV Amine fromAldrich 56

cHept 3-OCH₃ rac 0.37 (D) Carboxylic acid: Ex. No. LXV Amine fromAldrich 57

cHept 4-OCH₃ rac 0.24 (B) Carboxylic acid: Ex. No. LXV Amine fromAldrich 58

cHept 2-O—CH₂—CH═CH₂ rac 0.51 (C) Carboxylic acid: Ex. No. LXV Amine:Ex. No. II 59

cHept 3-COhd 2CH₃ rac 0.73 (C) Carboxylic acid: Ex. No. LXV Amine: Ref.:F. M. Markwardt et al., Pharmazie 22, 465 (1967). 60

cHept 4-CO₂CH₃ rac 0.33 (B) Carboxylic acid: Ex. No. LXV Amine: Ref.: M.G. Nair and C. M. Baugh, J. Org. Chem. 38, 2185 (11973). 61

cHept 3-CH₃ rac 0.19 (B) Carboxylic acid: Ex. No. LXV Amine from Aldrich62

cHept 2-NO₂ rac 0.39 (B) Carboxylic acid: Ex. No. LXV Amine: Ref.: EP373 891 63

cHept 3-NO₂ rac 0.28 (B) Carboxylic acid: Ex. No. LXV Amine from Aldrich64

cHept 4-NO₂ rac 0.21 (B) Carboxylic acid: Ex. No. LXV Amine from Aldrich65

cHept 2-Cl rac 0.75 (D) Carboxylic acid: Ex. No. LXV Amine from Aldrich66

cHept 3-Cl rac 0.71 (D) Carboxylic acid: Ex. No. LXV Amine fromLancaster 67

cHept 4-Cl rac 0.61 (D) Carboxylic acid: Ex. No. LXV Amine from Aldrich68

cPent H rac 0.28 (D) Carboxylic acid: Ex. No. LXI Amine from Aldrich

Example 69

[0354]2-(R,S)-2-[4-(2,4-Dimethyl-5,6,7,8-tetrahydro-α-carbolin-9-yl)-methyl-phenyl]-2-cycloheptyl-aceticacid N-(2-hydroxybenzyl)amide

[0355] 0.60 g of the compound from Example 58 are boiled under refluxfor 22 hours with 33 mg of palladium (10% on animal carbon) and 33 mg ofpara-toluenesulphonic acid monohydrate in 3 ml of methanol and 0.6 ml ofwater under argon as a protective gas. If reaction is incomplete (TLCchecking, dichloromethane:ethanol=50:1), 33 mg of palladium (10% onanimal carbon) and 33 mg of para-toluenesulphonic acid monohydrate areadded once more and the mixture is boiled under reflux for a further 24hours. The catalyst is filtered off hot with suction and washed withplenty of hot methanol, and the filtrate is evaporated. After drying ina high vacuum over phosphorus pentoxide, 0.52 g of product are obtained.

[0356] R_(f)=0.33 (dichloromethane:ethanol=50:1)

Example 70

[0357]2-(R,S)-2-[4-(3-Hydroxymethyl-β-carbolin-9-yl)-methyl-phenyl]-2-cyclo-pentyl-aceticacid N—(R)-phenylglycinolamide

[0358] 500 mg (0.868 mmol) of the compound from Example 31 are treateddropwise with 1.737 ml (1.737 mmol) of a 1 M lithium aluminium hydridesolution in tetrahydrofuran under argon at 0° C. in 5 ml of anhydroustetrahydrofuran and stirred at about 20° C. for 4 h. The reactionmixture is treated cautiously with 5 ml of water and adjusted to a pH ofabout 2 using 2 M aqueous hydrochloric acid. The aqueous phase isextracted several times with diethyl ether and dichloromethane, driedwith sodium sulphate and evaporated. The crude product is purified bychromatography on silica gel 60 (Merck, dichloromethane todichloromethane:methanol=50:1).

[0359] Yield: 0.12 g

[0360] R_(f)=0.26 (dichloromethane:ethanol=20:1)

[0361] The compounds of Table 4 are prepared in analogy to the procedureof Example 70: TABLE 4

Ex. No. Y 1 R_(f) (solvent) Starting material 71 4-CH₂OH rac 0.47 (C)Ex. No. 60 72 3-CH₂OH rac 0.26 (C) Ex. No. 59

Example 73

[0362]2-(R,S)-2-[4-(2,4-Dimethyl-5,6,7,8-tetrahydro-α-carbolin-9-yl)-methyl-phenyl]-2-cycloheptyl-aceticacid N-(4-carboxybenzyl)amide

[0363] 0.325 g (0.55 mmol) of the compound from Example 60 is reacted at60° C. with 0.5 ml of aqueous 2 M sodium hydroxide solution in 3 ml ofmethanol for 18 h. If the reaction is still not complete according tothin-layer analysis (solvent F), a further 0.5 ml of aqueous 2 M sodiumhydroxide solution in 1 ml of methanol is added and the mixture is thenboiled under reflux for 24 h. The reaction mixture is cooled andadjusted to a pH of about 4 using 1 M hydrochloric acid, and theprecipitate which is deposited is filtered off with suction, washed withwater and petroleum ether:diethyl ether=5:1 and freed from the residualsolvents in a high vacuum over phosphorus pentoxide.

[0364] Yield: 0.154 g

[0365] R_(f)=0.50 (dichloromethane:methanol:acetic acid=90:10:2)

Example 74

[0366]2-(R,S)-2-[4-(2,4-Dimethyl-5,6,7,8-tetrahydro-α-carbolin-9-yl)-methyl-phenyl]-2-cycloheptyl-aceticacid N-(3-carboxybenzyl)amide

[0367] The title compound can be prepared from the compound of Example59 analogously to the procedure of Example 73.

[0368] R_(f)=0.27 (dichloromethane:ethanol=20:1)

[0369] The compounds shown in Tables 5, 6, 7, 8, 9 and 10 are preparedin analogy to the procedure of Example 1: TABLE 5

Ex. No. Y 1 M.p. Starting material 75 3-OH rac 177-178 Carboxylic acid:Ex. No. LXII Amine: US 43 88 250 76 4-OH rac 183-184 Carboxylic acid:Ex. No. LXII Amine: Ref.: C. Hartmann and J.P. Klinman, Biochemistry 30,4605 (1991)

[0370] TABLE 6

Ex. No. R⁵ R_(f) (solvent) Starting material 77

0.20 (C) Carboxylic acid: Ex. No. LXV Amine from Aldrich 78

0.12 (C) Carboxylic acid: Ex. No. LXV Amine from Aldrich 79

0.19 (C) Carboxylic acid: Ex. No. LXV Amine from Aldrich 80

0.24 (D) Carboxylic acid: Ex. No. LXV Amine from Aldrich

[0371] TABLE 7

Ex. No. 1 −R²⁰ R_(f) (solvent) Starting material 81 rac

0.10 (P) Acid: Ex. No. LXXIX Amine from Aldrich 82 rac

0.28 (P) Acid: Ex. No. LXXIX Amine from Aldrich

[0372] TABLE 8

Starting material M.p. a) Reference (° C.) b) Distributor Ex. R_(f) c)Synthesis No. 1 X Y (solvent) MS (FAB) from Ex. No. 83 rac 3-OCH₃ 4-OCH₃179 562 Carboxylic acid: 0.50 (A) (100%) c) Ex. No. LXI 154 Amine from(80%) Aldrich. 84 rac 3-CH₃ 5-CH₃ 212 530 Carboxylic acid: 0.60 (B)(100%) c) Ex. No. LXI Amine from Emka-Chemie. 85 rac 3-Cl 5-Cl 212 570Carboxylic acid: 0.18 (M) (100%) c) Ex. No. LXI 196 (50%) Amine fromMaybridge. 86 rac 3-OH 4-OH 137 534 Carboxylic acid: 0.39 (A) (100%) c)Ex. No. LXI 307 (60%) Amine from Aldrich. 87 rac 3-OCH₃ 4-OH 135 548(80%) Carboxylic acid: 0.65 (A) 154 c) Ex. No. LXI (100%) Amine fromAldrich.

[0373] TABLE 9

Starting material* a) Reference Ex. M.p. (° C.) b) Distributor No. 1 DR_(f) (solvent) MS (FAB) c) Synthesis from Ex. No 88 rac iPr 210 506(100%) Carboxylic acid: 0.37/0.31 154 (60%) Ex. No. LXXXII (A) 89 raciBu — 520 (100%) Carboxylic acid: 0.30 (A) 154 (50%) Ex. No. LXXX

[0374] TABLE 10

M.p. (° C.) Starting material Ex. No. -Z -R²¹ R_(f) (solvent) from Ex.No. 90

188-189 LXXXIX 91

0.024 (P) LXXXIX 92

207-208 XC 93

211-212 XC

[0375] The compounds of Table 11 are prepared analogously to theprocedure of Example Nos. 1, 2 and 3: TABLE 11

Ex. M.p. (° C.) Starting material No. Z D 1 R_(f) (solvent) MS (FAB)from Ex. No. 94

cHept S 0.23 (B) 27 95

cHept R 0.17 (B) 27 96

cPent S 0.29 (A) 20 97

cPent R 0.29 (A) 20 98

cHex S 0.23 (D) 38 99

cHex R 0.21 (D) 38 100

iPr S 208° C. 506 (100%) 154 (40%) 88 101

iPr R 204° C. 506 (100%) 154 (40%) 88 102

iBu S 182° C. 89 103

iBu R 206° C. 89 104

cPent rac 0.34 (C) CV 105

cPent rac 0.44 (E) 0.56 CVI 106

cPent S 0.56 (E) 586 (100%) 154 (94%) CVI 107

cPent R 0.44 (E) CVI 108

rac 0.26 (E) 0.31 CVII 109

cPent S 0.55 (C) CVII 110

cPent R 0.57 (C) CVII 111

cPent rac 0.45 (C) CVIII 112

cPent rac 0.4 C CIX 114

cPent rac 0.37 C CX 115

cPent S 0.37 (C) CX 116

cPent diaA 194° C. 81 117

cPent diaB 137° C. 81

[0376] The compounds of Table 12 are prepared analogously to theprocedure of Example Nos. 1, 2 and 3: TABLE 12

Ex. M.p. (° C.) Starting material No. 1 R²² R_(f) (solvent) MS (FAB)from Ex. No. 118 rac

0.82 (C) 574 (100%) LXI 119 rac

0.57 (C) 0.62 576 (100%) LXI 120 rac

0.43 (C) 0.48 LXI 121 rac

0.52 (C) LXI 122 rac

0.47 (C) LXI 123 rac

0.17 (D) 0.32 LXI 124 rac

0.43 (C) LXI 125 rac

0.57 (C) LXI 126 rac

0.41 (C) LXI 127 rac

0.14 (C) 137 128 S

187° C. 548 (100%) 154 (80%) 137 (85%) LXI

[0377] The compounds of Table 13 are prepared analogously to theprocedure of Example No. 73: TABLE 13

Example No.

X Y Z M.p. [° C.]R_(f) (solvent) Starting material from Ex. No. 129rac/rac H H H 0.15 (S) 118 130 rac/rac H OH H 0.18 (T) 119 0.24 131rac/rac H H OH 0.68 (S) 120 0.76 132 rac/rac OH H H 0.16 (T) 121 0.24

[0378] The compounds of Table 14 are prepared analogously to theprocedure of Example No. 70: TABLE 14

Example No.

X Y Z M.p. [° C.]R_(f) (solvent) Starting material from Ex. No. 133rac/rac H OH H 0.30 (A) 119 134 rac/rac H H OH 0.25 (A) 120 135 rac/racOH H H 0.33 (A) 121 136 rac/rac H OH OH 0.23 (A) 122 137 rac/rac H H NH₂0.31 (C) 125

Example No. 138

[0379]2-(R,S)-2-[4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-aceticacid N-[1-(R,S)-1-(4-acetamido-phenyl)-2-hydroxy-ethyl]amide

[0380] Part A)

[0381] 0.60 g (1.10 mmol) of the compound from Example No. 137 istreated with 192 μl (3.29 mmol) of triethylamine in 10 ml ofdichloromethane and then reacted at 0° C. with 70 μl (0.99 mmol) ofacetyl chloride. After a stirring time of 3 hours, in which the reactiontemperature rises to 20° C., the mixture is shaken successively with 1 Mhydrochloric acid, 0.1 M aqueous sodium hydroxide solution and water,and the organic phase is dried with magnesium sulphate and evaporated.

[0382] Part B)

[0383] The crude product thus obtained shows a double acetylation (631,57%, M⁺+H/653, 6%, M⁺+Na) in the mass spectrum (FAB). It is thereforereacted with 2 M sodium hydroxide solution at 20° C. for one hour in 6ml of methanol. The pH is then adjusted to 2 using 1 M hydrochloric acidand the mixture obtained is extracted with ethyl acetate. The organicphase is washed with water until neutral, dried with magnesium sulphateand evaporated in vacuo. Drying in a high vacuum yields 0.28 g ofproduct.

[0384] R_(f)=0.17 (Dichloromethane:ethanol=20:1)

Example No. 139

[0385]2-(R,S)-2-[4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-aceticacid N-[1-(R,S)-1-(4acetamido-phenyl)-2-acetoxy-ethyl]amide

[0386] If the compound from Example No. 137 is reacted with 4equivalents each of triethylamine and acetyl chloride analogously toPart A of the procedure from Example No. 138, the title compound isobtained.

[0387] R_(f)=0.56 (Dichloromethane:ethanol 20:1)

[0388] The compounds of Table 15 are prepared analogously to theprocedure of Example No. 138: TABLE 15

Example No.

R²³ M.p. [° C.]R_(f) (solvent) Starting material from Ex. No. 140rac/rac nBu 0.49 (A) 137 141 rac/rac Et 0.81 (U) 137

Example No. 142

[0389]2-(S)-2-[4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-aceticacid N-[1-(R)-1-phenyl-2-acetoxy-ethyl]amide

[0390] 4.5 g (8.46 mmol) of the compound No. 2 are suspended in 300 mlof dichloromethane, treated with 2.05 ml (25.4 mmol) of pyridine and1.82 ml (25.4 mmol) of acetyl chloride in 30 ml of dichloromethane andreacted at 20° C. for 20 hours. The mixture is extracted with buffer(Merck) of pH=2 and water, dried with sodium sulphate and evaporated.After precipitating by stirring with methanol and subsequently drying ina high vacuum over phosphorus pentoxide, 3.6 g of product are obtained.

[0391] R_(f)=0.62 (Petroleum ether:ethyl acetate=1:1)

[0392] The compounds of Table 16 are prepared analogously to theprocedure of Example No. 142: TABLE 16

Starting Exam- material ple M.p. [° C.] from No. R²⁴ R_(f) (solvent) Ex.No. 143 -Et 0.25 (D) 2 144 —CH₂OAc 0.29 (D) 2 145 —CH₂OCH₂Ph 0.27 (D) 2146 cis-(CH₂)₇—Z—CH═CH—(CH₂)₇CH₃ 0.52 (D) 2 147 —(CH₂)₁₄—CH₃ 0.69 (G) 2148 -Ph 0.65 (C) 2 149

2 150 -tBu 0.38 (C) 2

Example No. 151

[0393]2-(S)-2-[4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2cyclopentyl-thioaceticacidN-[1-(R)-1-phenyl-2-acetoxy-ethyl]amide

[0394] 1.5 g (2.6 mmol) of the compound from Example No. 142 are treatedwith 1.27 g (3.13 mmol) of2,4-bis-(4-methoxyphenyl)-1,3dithia-2,4-diphosphetane-2,4-disulphide(Lawesson's reagent) in 50 ml of dioxane and boiled under reflux for 5hours. The reaction mixture is evaporated to dryness in vacuo andpurified by chromatography on silica gel MATREX^(TR) silica Si (Amicon,Grace Company/20μ/MPLC column/dichloromethane:ethanol=100:1); yield: 665mg.

[0395] R_(f)=0.53 (Petroleum ether:ethyl acetate=2:1)

[0396] MS (FAB): m/e=612 (4%, [M+Na]⁺), 590 (100%, [M+H]⁺), 529 (19%,M⁺−AcOH).

Example No. 152

[0397]2-(S)-2-[4-(2,4Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-aceticacid N-[1-(R)-1-phenyl-2-[2-hydroxy-acet)-oxy]-ethyl]amide

[0398] 1.45 g (2.13 mmol) of the compound from Example No. 145 arehydrogenated with hydrogen on palladium (5% on animal carbon) at 20° C.and normal pressure in 100 ml of THF. After 18 hours, the mixture isfiltered off with suction through kieselguhr, washed several times withmethanol and dichloromethane, and the combined organic solutions areevaporated. The solid residue is stirred with pentane, filtered off withsuction and freed from the residual solvent in a high vacuum.

[0399] R_(f)=0.31 (Petroleum ether:ethyl acetate=1:1)

Example No. 153

[0400]2-(S)-2-[4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-thioaceticacidN-[1-(R)-1-phenyl-2-hydroxyethyl]-amide

[0401] The title compound is prepared at 20° C. from the compound ofExample No. 151 in DME as a solvent analogously to the synthesisprocedure from Example No. 73.

[0402] R_(f)=0.24 (Dichloromethane:ethanol=50:1)

Example No. 154

[0403]2-[4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-aceticacid N-[1-(thien-2-yl) 1-methoxycarbonyl-methyl]-amide

[0404] The title compound is prepared from the compound of Example No.LXII and (R,S)— (thien-2-yl)-glycine methyl ester analogously to thesynthesis procedure of Example Nos. 1, 2 and 3.

[0405] R_(f)=0.67 (Dichloromethane:ethanol=20:1)

Example No. 155

[0406]2-[4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-aceticacid N-[1-(thien-2-yl)2-hydroxy-ethyl]-amide

[0407] The title compound is prepared from the compound of Example No.154 analogously to the synthesis procedure of Example No. 70.

[0408] R_(f)=0.21 (Dichloromethane:ethanol=50:1)

Example No. 156

[0409]2-(S)-2-[4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-aceticacid N-[1-(R)-1-phenyl-2-(2,4,6-trimethyl-benzoyl-oxy)ethyl]-amide

[0410] The compound is prepared from Example No. 2 is reacted to givethe title compound analogously to the procedure of Example No. 142.

[0411] R_(f)=0.26 (Mobile phase D)

Example No. 157

[0412] 1-(R,S)-1-Phenyl-2-triphenylmethyloxy-ethyl2-(R,S)-2-[4-(2,4dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-acetate

[0413] 1.0 g (2.42 mmol) of the compound from Example LXI is reactedwith 1 ml (7.27 mmol of triethylamine and 206 μl (2.67 mmol) of mesylchloride in 30 ml of DMF at −30° C. for 2 h, then treated dropwise witha solution of 1.1 g (2.9 mmol) of the compound from Example No. CXI and296 mg (2.42 mmol) of DMAP in 10 ml of DMF and stirred for about 20 hwhile gradually warming to 20° C. For working up, the mixture is stirredinto ether/water, the phases are separated, and the organic phase isextracted with aqueous 1 M sodium hydroxide solution and washed withwater. The organic phase is dried with magnesium sulphate andevaporated—finally in a high vacuum; yield: 1.0 g.

[0414] R_(f)=0.44 (Petroleum ether:ethyl acetate=5:1)

Examples 158 and 159

[0415] 1-(R,S)-1-Phenyl)2-triphenylmethyloxy-ethyl[2-(R,S)-2-[4-(2,4-dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-acetate

[0416] 1.0 g (1.29 mmol) of the compound from Example No. 157 is stirredwith 5 ml of trifluoroacetic acid in 10 ml of THF and 5 ml of water at20° C. for 48 h. The mixture is then stirred with 300 ml of ether and200 ml of aqueous sodium hydrogen carbonate solution, the phases areseparated after evolution of carbon dioxide has subsided and the organicphase is extracted with buffer of pH=7 (Merck) and dried with magnesiumsulphate. After evaporating the solvents, a crude product is obtainedwhich is purified by chromatography on silica gel (Merck/petroleumether:ethyl acetate=5:1) and separated into the diastereomers.

[0417] Racemic diastereomer A)

[0418] Yield: 300 mg

[0419] R_(f)=0.54 (Petroleum ether:ethyl acetate=2:1)

[0420] Racemic diastereomer B)

[0421] Yield: 320 mg

[0422] R_(f)=0.42 (Petroleum ether:ethyl acetate=2:1) TABLE 17

Ex. Position Starting material No. Z (o, m or p) {circle over (1)} DR_(f) (solvent) MS Ex. No. 160

p — H 0.30 (C) FAB: 464 (100%) CXLI 161

p rac cPent 0.35 (C) FAB: 504 (95%) CXLII 162

p S cPent 0.35 (C) CXLII 163

p R cPent 0.35 (C) CXLII 164

p rac cPent 0.23/(C) 0.25 FAB: 518 (51%) CXLIII 165

p R cPent 0.29 (C) CXLIII 166

p S cPent 0.25 (C) CXLIII 167

m rac cPent 0.40 (C) FAB: 532 (100%) CXLIV 168

p rac cPent 0.26/0.22 (D) FAB: 518 (100%) CVL 169

p cPent 0.26 (D) CVL 170

p cPent 0.22 (D) CVL 171

p rac cPent 0.37 (C) CVLI 172

p rac cPent CVLII 173

p rac cPent 0.19 (C) FAB: 532 (100%) CVLIII 174

p rac cPent CIL 175

p cPent CIL 176

p cPent CIL 177

p rac Et CI 178

p rac Me CLI 179

p rac nPent CLII 180

p diaA nPent CLII 181

p diaB nPent CLII 182

p rac

CLIII 183

p diA

CLIII 184

p diaB

CLIII

Example 185

[0423]2-(R,S)-2-[(4-(2,4Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2cyclopentyl-aceticacid [N-benzyl, N-benzoyl]-amide

[0424] 2.0 g(4.8 mmol) of the compound from Example No. LXI are reactedwith 0.74 ml (5.3 mmol) of triethylamine and 0.41 ml (5.3 mmol) of mesylchloride at −30° C. in anhydrous DMF for 1 h. A solution of 1.07 g (5.1mmol) of N-benzyl-benzamide and 1.42 ml (10.2 mmol) of triethylamine in10 ml of anhydrous DMF is then added dropwise at −30° C. and stirred for16 h while gradually warming to 20° C. The reaction mixture is stirredwith ether and water, the phases are separated and the aqueous phase iswashed after setting a pH of 4 and 7 in each case. The combined organicsolutions are evaporated and purified by chromatograhy on silica gel 60(Merck/first dichloromethane:ethanol=60:1; then petroleum ether:ethylacetate=4:1).

[0425] R_(f)=0.58 (Petroleum ether:ethyl acetate=2:1)

Example 186

[0426]2-(R,S)-2-[4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-aceticacid [N-benzoyl]-amide

[0427] 2.0 g (3.3 mmol) of the compound from Example No. 185 are reactedat 20° C. under a hydrogen pressure of about 1 bar on 2 g of palladiumon animal carbon (5%) in dioxane for about 40 h. The mixture is thenfiltered off with suction through a Seitz filter and washed withdioxane, and the filtrate is evaporated. The crude product isprecipitated by stirring with methanol at 60° C. and is filtered offwith suction at 20° C., washed with cold methanol and dried overphosphorus pentoxide in vacuo.

[0428] R_(f)=0.49 (Petroleum ether:ethyl acetate=2:1)

Example 187

[0429]2-(R,S)-2-[4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-aceticacid [N-(1-(R,S)-1-phenyl-1-ethoxycarbonyl-methyl]-amide

[0430] The compound from Example No. LXI is reacted to give the titlecompound analogously to the procedure of Example Nos. 1, 2 and 3.

Example 188

[0431]2-(R,S)-2-[4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-aceticacid [N-(1-(R,S)-1-phenyl-1-carboxy-methyl]-amide

[0432] The compound from Example No. 187 is reacted to give the titlecompound analogously to the procedure of Example No. 73.

Example 189

[0433]1-1-(R,S)-2-hydroxy-phenyl-ethyl2-(R,S)-2-[4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-acetate

[0434] 1 g (2.42 mmol) of the compound from Example No. LXI is reactedwith 1 ml (7.27 mmol) of triethylamine and 206 μl (2.67 mmol) of mesylchloride for 1 h in 30 ml of DMF at −30° C. A solution of1-(R,S)-1-phenyl-2-hydroxy-thioethanol in 10 ml of DMF is then addeddropwise at the temperature mentioned and the mixture is stirred for afurther hour. For working up, the reaction mixture is stirred into etherand aqueous sodium hydrogen carbonate solution. The organic phase iswashed with buffer pH=2 and then pH=7, dried with magnesium sulphate andevaporated. The crude product is purified on silica gel 60(Merck/petroleum ether:ethyl acetate=5:1); yield: 660 mg

[0435] R_(f)=0.58 (Petroleum ether:ethyl acetate=2:1)

1. Cycloalkano-indole and -azaindole derivatives of the general formula(I)

in which R¹ and R², including the double bond connecting them, togetherform a phenyl or pyridyl ring or a ring of the formula

wherein R⁸ denotes hydrogen or straight-chain or branched alkyl havingup to 4 carbon atoms, R³ and R⁴, including the double bond connectingthem, together form a phenyl ring or a 4- to 8-membered cycloalkene oroxocycloalkene radical, or ring systems mentioned under R¹/R² and R³/R⁴optionally being substituted up to 3 times by identical or differenthalogen, trifluoromethyl, carboxyl or hydroxyl substituents, bystraight-chain or branched alkoxy or alkoxycarbonyl each having up to 6carbon atoms or by straight-chain or branched alkyl having up to 6carbon atoms, which, for its part, can be substituted by hydroxyl or bystraight-chain or branched alkoxy having up to 4 carbon atoms, Drepresents hydrogen, cycloalkyl having 4 to 12 carbon atoms orstraight-chain or branched alkyl having up to 12 carbon atoms, Erepresents the —CO— or —CS— group, L represents an oxygen or sulphuratom or a group of the formula —NR⁹, wherein R⁹ denotes hydrogen orstraight-chain or branched alkyl having up to 6 carbon atoms, which isoptionally substituted by hydroxyl or phenyl, R⁵ represents phenyl or a5- to 7-membered saturated or unsaturated heterocycle having up to 3heteroatoms from the series consisting of S, N and/or O, the cyclesoptionally being substituted up to 3 times by identical or differentnitro, carboxyl, halogen or cyano substituents or by straight-chain orbranched alkenyl or alkoxycarbonyl each having up to 6 carbon atoms orby straight-chain or branched alkyl having up to 6 carbon atoms, whichis optionally substituted by hydroxyl, carboxyl or by straight-chain orbranched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms,and/or the cycles optionally being substituted by a group of the formula—OR¹⁰ or —NR¹¹R¹², wherein R¹⁰ denotes hydrogen or straight-chain orbranched alkyl or alkenyl each having up to 6 carbon atoms, R¹¹ and R¹²are identical or different and denote phenyl, hydrogen or straight-chainor branched alkyl having up to 6 carbon atoms or straight-chain orbranched acyl having up to 8 carbon atoms, which is optionallysubstituted by a group of the formula —NR¹³R¹⁴, wherein R¹³ and R¹⁴ areidentical or different and denote hydrogen or straight-chain or branchedacyl having up to 8 carbon atoms, R⁶ represents hydrogen, carboxyl orstraight-chain or branched alkoxycarbonyl having up to 5 carbon atoms,or represents straight-chain or branched alkyl having up to 6 carbonatoms, which is optionally substituted by hydroxyl or by a group of theformula —O—CO—R¹⁵, wherein R¹⁵ denotes phenyl which is optionallysubstituted up to 3 times by identical or different halogen or hydroxylsubstituents or by straight-chain or branched alkyl having up to 5carbon atoms, or straight-chain or branched alkyl or alkenyl each havingup to 22 carbon atoms, each of which is optionally substituted by agroup of the formula —OR¹⁶, wherein R¹⁶ is hydrogen, benzyl,triphenylmethyl or straight-chain or branched acyl having up to 6 carbonatoms, R⁷ represents hydrogen or R⁶ and R⁷ together represent the groupof the formula ═O, if appropriate in an isomeric form, and their salts.2. Cycloalkano-indole and -azaindole derivatives of the formulaaccording to claim 1 wherein R¹ and R², including the double bondconnecting them, together form a phenyl or pyridyl ring or a ring of theformula

wherein R⁸ denotes hydrogen or straight-chain or branched alkyl havingup to 3 carbon atoms, R³ and R⁴, including the double bond connectingthem, together form a phenyl ring or a cyclopentene, cyclohexene,cycloheptene, cyclooctene, oxocyclopentene, oxocyclohexene,oxocycloheptene or oxocyclooctene radical, or ring systems mentionedunder R¹/R² and R³/R⁴ optionally being substituted up to 2 times byidentical or different fluorine, chlorine, bromine, trifluoromethyl,carboxyl or hydroxyl substituents, by straight-chain or branched alkoxyor alkoxycarbonyl each having up to 4 carbon atoms or by straight-chainor branched alkyl having up to 4 carbon atoms, which, in turn, can besubstituted by hydroxyl or by straight-chain or branched alkoxy havingup to 3 carbon atoms, D represents hydrogen, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl or straight-chain or branched alkylhaving up to 10 carbon atoms, E represents the —CO— or —CS— group, Lrepresents an oxygen or sulphur atom or represents a group of theformula —NR⁹, wherein R⁹ denotes hydrogen or straight-chain or branchedalkyl having up to 5 carbon atoms, which is optionally substituted byhydroxyl or phenyl, R⁵ represents phenyl, pyridyl, furyl, thienyl orimidazolyl, each of which is optionally substituted up to 2 times byidentical or different nitro, carboxyl, fluorine, chlorine, bromine orcyano substituents, by straight-chain or branched alkenyl or alkoxycarbonyl each having up to 4 carbon atoms or by straight-chain orbranched alkyl having up to 5 carbon atoms, which is optionallysubstituted by hydroxyl, carboxyl or by straight-chain or branchedalkoxy or alkoxycarbonyl each having up to 5 carbon atoms, and/or thecycles are optionally substituted by a group of the formula —OR¹⁰ or—NR¹¹R¹², wherein R¹⁰ denotes hydrogen or straight-chain or branchedalkyl or alkenyl each having up to 4 carbon atoms, R¹¹ and R¹² areidentical or different and denote phenyl, hydrogen or straight-chain orbranched alkyl having up to 5 carbon atoms or denote straight-chain orbranched acyl having up to 6 carbon atoms, which is optionallysubstituted by a group of the formula —NR¹³R¹⁴, wherein R¹³ and R¹⁴ areidentical or different and denote hydrogen or straight-chain or branchedacyl having up to 6 carbon atoms, R⁶ represents hydrogen, carboxyl orstraight-chain or branched alkoxycarbonyl having up to 4 carbon atoms,or represents straight-chain or branched alkyl having up to 5 carbonatoms, Which is optionally substituted by hydroxyl or by a group of theformula —O—CO—R¹⁵, wherein R¹⁵ denotes phenyl which is optionallysubstituted up to 3 times by identical or different fluorine, chlorine,bromine or hydroxyl substituents or by straight-chain or branched alkylhaving up to 4 carbon atoms, or straight-chain or branched alkyl oralkenyl each having up to 20 carbon atoms, each of which is optionallysubstituted by a group of the formula —OR¹⁶, wherein R¹⁶ is hydrogen,benzyl, triphenylmethyl or straight-chain or branched acyl having up to5 carbon atoms, R⁷ represents hydrogen or R⁶ and R⁷ together representthe group of the formula ═O, if appropriate in an isomeric form, andtheir salts.
 3. Cycloalkano-indole and -azaindole derivatives of theformula according to claim 1 wherein R¹ and R², including the doublebond connecting them, together form a phenyl or pyridyl ring or a ringof the formula

wherein R⁸ denotes hydrogen or methyl, R³ and R⁴, including the doublebond connecting them, together form a phenyl ring or a cyclopentene,cyclohexene, cycloheptene, cyclooctene, oxocyclopentene, oxocyclohexene,oxocycloheptene or oxocyclooctene radical. or ring systems mentionedunder R¹/R² and R³/R⁴ optionally being substituted up to 2 times byidentical or different fluorine, chlorine, bromine, trifluoromethyl,carboxyl or hydroxyl substituents, by straight-chain or branched alkoxyor alkoxycarbonyl each having up to 3 carbon atoms or by straight-chainor branched alkyl having up to 3 carbon atoms, which for its part, canbe substituted by hydroxyl, methoxy or ethoxy, D represents hydrogen,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or straight-chain orbranched alkyl having up to 6 carbon atoms, E represents the —CO— or—CS— group, L represents an oxygen or sulphur atom or represents a groupof the formula —NR⁹, wherein R⁹ denotes hydrogen or straight-chain orbranched alkyl having up to 4 carbon atoms, which is optionallysubstituted by hydroxyl or phenyl, R⁵ represents phenyl, pyridyl orthienyl, each of which is optionally substituted up to 2 times byidentical or different nitro, carboxyl, fluorine, chlorine, bromine orcyano substituents, by straight-chain or branched alkenyl oralkoxycarbonyl each having up to 3 carbon atoms or by straight-chain orbranched alkyl having up to 4 carbon atoms, which is optionallysubstituted by hydroxyl, carboxyl or by straight-chain or branchedalkoxy or alkoxycarbonyl each having up to 4 carbon atoms, and/or thecycles are optionally substituted by a group of the formula —OR¹⁰ or—NR¹¹R¹², wherein R¹⁰ denotes hydrogen or straight-chain or branchedalkyl or alkenyl each having up to 3 carbon atoms, R¹¹ and R¹² areidentical or different and denote phenyl, hydrogen or straight-chain orbranched alkyl having up to 4 carbon atoms or denote straight-chain orbranched acyl having up to 5 carbon atoms, which is optionallysubstituted by a group of the formula —NR¹³R¹⁴, wherein R¹³ and R¹⁴ areidentical or different and denote hydrogen or straight-chain or branchedacyl having up to 5 carbon atoms, R⁶ represents hydrogen, carboxyl orstraight-chain or branched alkoxycarbonyl having up to 3 carbon atoms,or represents straight-chain or branched alkyl having up to 4 carbonatoms, which is optionally substituted by hydroxyl or by a group of theformula —O—CO—R¹⁵, wherein R¹⁵ denotes phenyl which is optionallysubstituted up to 3 times by identical or different straight-chain orbranched alkyl having up to 3 carbon atoms, or denotes straight-chain orbranched alkyl or alkenyl each having up to 19 carbon atoms, each ofwhich is optionally substituted by a group of the formula —OR¹⁶, whereinR¹⁶ denotes hydrogen, benzyl, triphenylmethyl or straight-chain orbranched acyl having up to 4 carbon atoms, R⁷ represents hydrogen or R⁶and R⁷ together represent the group of the formula ═O, if appropriate inan isomeric form, and their salts.
 4. Cycloalkano-indole and -azaindolederivatives according to claim 1 wherein such compound is2-[4-(2,4-dimethyl-5,6,7,8-tetrahydro-α-carboline-9-yl)-methyl-phenyl]-2-cyclopenthyl-aceticacid N-[(R)-phenylglycinolamide] of a formula

in form of their isomeres their recamic mixtures and salts thereof. 5.Cycloalkano-indole and -azaindole derivatives according to claim 1wherein such compound is2-[4-(2,4-dimethyl-α-carboline-9-yl)-methyl-phenyl]-2-cyclopenthyl-aceticacid N-[(R)-phenylglucynolamide] of the formula

in form of their enanciomeres their racemates and salts thereof. 6.Cycloalkano-indole and -azaindole derivatives according to claim 1wherein such compound is1-(R,S)-1-Phenyl)-2-triphenylmethyloxy-ethyl[2-(R,S)-2-[4-(2,4-dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-acetateof the formula

in form of their isomeres, their racemates and salts thereof. 7.Cycloalkano-indoles and -azaindoles according to clain 1 wherein suchcorn pound is2-(R,S)-2-[4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-aceticacid [N-(1-(R,S)-1-phenyl-1 carboxy-methyl]-amide of the formula

in form of their isomeres, their racemates and salts thereof.
 8. Acomposition for the treatment of ateroscleroses comprising an amounteffective therefor of a compound or salt thereof according to claim 1and a pharmacologically ecaptable diluent.
 9. The method of treatingateroscleroses in a pationt in need thereof which comprisesatministering to such patient an amount effective therefor of a compoundor salt thereof according to claim 1.